Chaperon-Mediated Autophagy in Cancer Biology: Term Paper

POLYTECHNIC UNIVERSITY OF THE PHILIPPINES COLLEGE OF SCIENCE DEPARTMENT OF BIOLOGY
Chaperon-Mediated Autophagy in Cancer Biology

TERM PAPER
Diana Amor Jaguio, Nelly Mariz Pineda, Aljohn
3/10/2012
Cancer What is cancer? Cancer is an invasive distensions spreading crab-like as described by Hippocrates. From the word crab; karkinos in Greek and cancer in Latin; came the name of the disease and the name of its inducing agents, carcinogens. Cellular biologists had identified cancer with abnormal cell growth in the mid nineteenth century (Auyang).
Cancer is a potentially fatal disease caused mainly by environmental factors that mutate genes encoding critical cell-regulatory proteins. The resultant aberrant cell behavior leads to expansive masses of abnormal cells that destroy surrounding normal tissue and can spread to vital organs resulting in disseminated disease, commonly a harbinger of imminent patient death (Alison, 2001; Auyang). The cancerous cells may occur in liquids, as in leukemia. Mostly, however, occur in solid tumors that originally appear in various tissues in various parts of the body. By their original locations they are classified into various types of cancer, such as lung, colon, breast, or prostate cancer (Auyang).
Although cancer is an ancient disease that afflicts humans and other animals, its prominence in the Western world rose from the nineteenth century to become a disease of civilization (Auyang). Cancer is primarily a disease of elders; its risk
increases roughly as the fourth power of age (Alison, 2001; Auyang). And it is the
Polytechnic University of the Philippines College of Science Department of Biology Amor Jaguio Pineda BS Biology 4-2
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second-largest common diseasemalignant tumors. Coronary disease and cancer together are responsible for over 80% of all deaths in industrialized countries (Rath, 2001).
The overall 5-year survival rate of many cancers, including liver, lung, pancreas, bone, and advanced breast cancer, has not increased in the past 30 years. On a worldwide basis, cancer is fast replacing heart disease as the number one cause of death in adults (Lam, 2003).
Incidences of cancer keep increasing on a global scale (Rath, 2001). Since 1950, the overall cancer incidence, particularly in America, has increased by 44%, with breast cancer and male colon cancer up by 60% and prostate cancer up by 100%. 44% of Americans living today are expected to develop cancer (Lam, 2003). That is why Americans have poured roughly $200 billion, in inflation-adjusted dollars, into cancer research and cancer drug development between 1971 and 2004. Almost one-half of the bills went to several government agencies, the balance to philanthropies and pharmaceutical companies (Auyang).
In 1986, the director of National Cancer Institute predicted the eradication of cancer by 2000. Reality was not anywhere close. In 2004, a new director envisioned the elimination of the suffering and death due to cancer by 2015. The World Health
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Organization estimated that if unchecked, annual global cancer deaths could rise to 15 million by 2020 (Auyang).
What causes cancer? Cancers evolve through a complicated web of multiple causes and that it is not only pointless, but also counterproductive, to attempt to assign certain exposures a certain role in causing cancer (Clapp et. al., 2005).
In 1981, Doll and Peto produced a summary table that estimated that 2% of cancer deaths were due to pollution and 4% to occupation, with ranges of acceptable estimates of less than 1% to 5% for the pollution contribution and 2 to 8% for the occupation contribution. In this same table, they estimate that the proportion of cancer deaths due to tobacco is 30% and to diet, 35%. A variety of other factors, including alcohol, food additives, reproduction and sexual behavior, industrial products, medicines, geophysical factors, and infection are ascribed percentages. The sum of the individual percentages is 97%, with a final category of unknown with no percentage (Clapp et. al., 2005).
Cancer is a complex genetic disease that is caused primarily by environmental factors. The cancer-causing agents (carcinogens) can be present in food and water, in the air, and in chemicals and sunlight that people are exposed to. More signicantly, a globalization of unhealthy lifestyles; particularly cigarette smoking and the adoption of
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many features of the modern world Western diet (Alison, 2001; Auyang). The other factors include emotional stress, infections, lack of oxygen, poor nutrition, genetic mutation and environmental pollutants (Alison, 2001; Lam, 2003).
Only about one percent of cancers are unmistakably inherited. Strong genetic dispositions contribute to a small portion of adult cancers; actually, it contributes significantly 5-13 percent in cancer incidences (Clapp et. al., 2005; Auyang). Hormone production during reproductive cycles and other internal factors can also contribute (Auyang; Lam, 2003).
Inherited genetic defects account for some rare childhood cancers. Variations in genetic predisposition partly explain why some people are more susceptible than others are to a particular environmental carcinogen. Many genes involved are not cancer genes; they do not themselves induce cancer. Rather, they code for enzymes with vital normal functions, mainly to metabolize chemicals, breaking them down for excretion (Auyang).
The vast majority of cancers are attributable to what people eat and inhale, how they behave, their working conditions, viruses and bacteria, and natural and artificial radiation and chemicals (Clapp et. al., 2005; Auyang); actually, Tobacco use and diet each account for about 30% of new cancer cases, with infection associated with a
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further 15%; thus, much of cancer is preventable (Alison, 2001). These are usually called environmental risk factors for cancer (Auyang).
However, Rath said in his book, the origin of disease can be considered from two cellular aspects: The lack of biological fuel needed by the cells power plants, the mitochondria, or a failure in the function of the nucleus, the metabolic control center of the cell; programming error causes uncontrolled cell multiplication, and at the same time programming error causes a disruption of the organization of the surrounding connective tissue, which enables the diseased cells to spread (2001).
How does it spread in the body? Cancer does not develop overnight, instead often evolving over many years (Alison, 2001; Auyang) with detectable premalignant lesions presaging the development of full-blown malignancy (Alison, 2001).
Cancer cells move through the body with the presence of the cells that are capable of temporarily dissolving the surrounding tissuethe collagen and elastic fibers -so it can make its way through. For this purpose the cells use enzymes that can temporarily digest and weaken the connective fibers surrounding them. All forms of cancer spread with the help of the tissue-dissolving mechanism. The toxins entering the body from the diet, such as pesticides and preservatives, are the most common cause of liver cancer. Also, all pharmaceutical drugs have to be detoxified in the liver.
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Research has established that the more enzymes a cancer cell produces, the more aggressively the cancer develops. The faster the cancer can spread through a body, the shorter the life expectancy of the patient if the mechanism is not stopped (Rath, 2001).
The collagen-dissolving mechanism also plays a major role in the spread of cancer and the growth of secondary tumors in other organs or parts of the body (metastasis). Small blood vessels provide oxygen and nutrients to tumor cells. The walls of these blood capillaries are not obstacles for a cancer cell. With the help of collagendigesting enzymes, a cancer cell can eat its way into the lumen of the small blood vessel and into the blood stream. The blood can then carry away cancer cells, by which they can spread and invade other organs (Rath, 2001).
According to Lam, it is the body terrain that determines how the cancer is expressed. The root of cancer therefore lies in the progress of growth and metastasis, and not the tissue in which the tumor was first detected (2003).
Metastasis is the process where cancer cells invading the surrounding tissues, entering the blood stream, spreading and establishing colonies in distant parts of the body (Auyang). Tumors not only invade surrounding tissue, but are able to colonize other, often vital, organs, in this process. Widespread metastatic disease is usually a harbinger of imminent patient death (Alison, 2001).
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What are the kinds of cancer? Cancer can either benign or malignant. Benign tumours are generally slowgrowing expansive masses that compress rather than invade surrounding tissue. As such they generally pose little threat, except when growing in a conned space like the skull, and can usually be readily excised. However, many so-called benign tumours have malignant potential, notably those occurring in the large intestine, and these should be removed before malignancy develops. Malignant tumors are usually rapidly growing, invading surrounding tissue and, most signicantly, colonizing distant organs. The ability of tumour cells to detach from the original mass (the primary tumour) and set up a metastasis (secondary tumour) discontinuous with the primary is unequivocal proof of malignancy. Tumours are also classied according to their tissue of origin; recognition of the parent tissue in a lymph node metastasis could establish the location of a hitherto undiagnosed primary tumour (Alison, 2001).
Cancers that are not inherited are called sporadic. This means not that they have no genetic component but that their genetics occurs not in germ cells but in somatic cells, which constitute the bulk of our body. Some somatic cells, such as
muscle cells or neurons in the brain, stop dividing upon maturity. They can grow bigger in size or establish more connections, but their numbers do not multiply. Cancer
seldom if ever appears in such non-dividing cells. It appears in tissues where cells die and are replenished by new cell divisions (Auyang).
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What are the cures for cancer? According to Lam in 2003, there is no single cure for cancer and none is proposed. For the past 50 years, war on cancer has been fought with three tools surgery (cut), radiation therapy (burn), and chemotherapy (poison). Localized tumors can be removed by surgery or irradiation with high survival rates (Auyang). Benign tumours can normally be removed by surgery. Malignant solid tumors will, if possible, be surgically resected, probably followed and even preceded by other treatment modalities. If the tumour is amenable to surgery, then surgery is the single most effective tool in the anticancer armamentarium. Targeted radiotherapy is another option, as are combinations of anticancer drugs (Alison, 2001).
Most conventional anticancer drugs have been designed with deoxyribonucleic acid (DNA) synthesis as their target. Therein lies the problem, in that tumor cells are not the only proliferating cells in the body; cells that line the alimentary tract, bone marrow cells that generate red blood cells and cells to ght infection, and epidermal cells including those that generate hair are all highly proliferative. Thus, patients with cancer receiving chemotherapy commonly suer unwanted (hair loss) and sometimes potentially life-threatening side eects that limit treatment (Alison, 2001).
At a cellular level cancer is a very rare disease given that an individual has many millions of cells, so normally the repair and/or elimination mechanisms of damaged cells must be very ecient, asking to have a caretaker function. To account for the multiple
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mutations in cancer cells, attention has become focused on the mechanisms of DNA metabolism that maintain genome integrity, looking for the so-called mutator phenotype. If the mechanisms of DNA repair are faulty, this leads to genetic instability, facilitating an increased rate of alterations in the genome (Alison, 2001).
However, naturally oriented physicians think of the body as a closed internal ecosystem, and believe that it is the dysfunction of this ecosystem that is primarily responsible for the development of cancer. According to him, no treatment,
conventional or otherwise, can completely eliminate all cancer cells. The reason is simple. Cancer is a systemic disease, and there are simply too many cancerous or procancerous cells within the ecosystem of the body. Cancer is not a localized problem but a whole-body phenomenon of metastatic growth. Its growth process is affected by biological conditions. He then, therefore proposed fights against cancer by optimizing the internal terrain and enabling the patients internal system to destroy the tumor. It enhances the patients health so that cancer cells cannot grow and multiply (Lam, 2003).
Rath proposed a way of preventing the spread of the cancer cells. He said that the nature itself provides us with two large groups of molecules that can block collagen digestion and its dissolving actions which lead to the spread of cancer. The first group is the bodys intrinsic enzymatic block that can stop the action of collagen-digesting enzymes in a few moments. The second group is the enzyme- blocking substances that
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come from our diet or as dietary supplement. The most important one in this group is the natural amino acid L-lysine. When lysine is supplied in a sufficient amount as a dietary supplement; it can block the anchor sites in the connective tissue that collagendigesting enzymes use to attach themselves to the tissue. In this way lysine prevents these enzymes from uncontrollably disintegrating connective tissue (2001).
Lam said that, the use of non-toxic natural therapies has achieved huge successes over the past few decades. Extensive studies have proven them to have an edge over conventional therapies success rate of natural treatment is so much better than for many conventional cancer treatments (2003).
More than cures, scientists are cautiously optimistic about the possibility of improving early detection and prevention of cancer. Cancer takes several steps and a long time to develop. Its long latent period gives many opportunities to catch cells in their early stages of mutation and intervene to stop cancer progression. For instance, the pap smear followed by surgical removal of detected lesions have reduced death rate of cervical cancer by almost 80 percent. To extend the success in cervical cancer to cancer in general, scientists strive to identify biological markers that can finger incipient cancerous cells and predict whether they will evolve to significant cancer (Auyang).
Alison said that, no individual can guarantee not to contract the disease, but it is so strongly linked to diet and lifestyle that there are plenty of positive steps that can be
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taken to reduce the chances: eat more fruit and vegetables, reduce the intake of red meat and denitely do not smoke. Carcinogens interact with the individuals constitution, both inherited and acquired, determining vulnerability to cancer induction (2001).
Chaperone-Mediated Autophagy Chaperone-mediated autophagy (CMA) is an intracellular catabolic pathway that mediates the degradation of a selective subset of cytosolic proteins in lysosomes. Autophagy or self-eating is broadly used to designate the lysosomal delivery and degradation of intracellular components (Yang and Klionsky, 2010). Various types of autophagy co-exist in almost all cells, and they can be differentiated by the mechanisms that mediate the delivery of cargo to lysosomes. Macroautophagy and microautophagy are kinds of the autophagic process, in which entire regions of cytosol or selective cytosolic components are sequestered in vesicular compartments. Lysosomal enzymes can gain access to the enclosed cargo through direct fusion of the vesicles with lysosome, or by internalization of cargo-containing vesicles that form at the lysosomal membrane. A third form of autophagy, solely dedicated to degradation of soluble proteins can also be detected in most cell types in mammals. This autophagic process, known as chaperone-mediated autophagy, differs from the other forms of autophagy in both the way in which cargo proteins are recognized for lysosomal delivery and the way in which these proteins reach the lysosomal lumen (Dice, 2007; Cuervo, 2010).
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CMA is a process activated during long term starvation in which cells selectively degrade proteins in order to recycle their amino acids or use them for energy. During nutrient deprivation, substrates that contain a consensus motif related to KFERQ are recognized by a chaperone-cochaperone complex containing the heat shock cognate protein of 70 kDa (hsc70). Once this chaperone-cochaperone complex binds the substrate, it docks on the lysosomal membrane via a receptor known as the lysosomal associated membrane protein 2a or lamp2a. The substrate then is unfolded, presumably by the chaperone-cochaperone complex, translocated into the lumen with the help of a lysosomal isoform of hsc70, and degraded. Like most organelle protein import pathways, CMA is saturable as well as temperature-dependent. The substrates for CMA also compete with one another for binding and import, which provides an experimental method for discovering new substrates. There have been several substrates identified for CMA including ribonuclease A and glyceraldehyde 3-phosphate dehydrogenase (GAPDH).
The cytosolic chaperones and co-chaperones that participate in CMA are also involved in other intracellular pathways this was according to Chiang et al., 1989. According to Cuervoet al., (1997), the chaperones located in the lysosomal lumen or associated to the lysosomal membrane namely lys-Hsc70, membrane associated Hsc70 and lys-Hsp90 appear to be exclusively dedicated to CMA. However, as these are post-translational variations of cytosolic chaperones rather than independent gene
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products, regulating their expression does not provide a mean for selectively affecting CMA activity.
Moreover, Cuervo and Dice (1996) determined that LAMP-2A, the membrane protein that acts as a receptor for the CMA substrates has often been manipulated to regulate CMA activity. In fact, levels of LAMP-2A at the lysosomal membrane directly determine rates of CMA activity, because substrate binding to the cytosolic tail of LAMP-2A is a limiting step in CMA. Eskelinenet al., (2005) added that LAMP-2A is a spliced variant of a single Lamp2 gene, which also encodes two other variants, LAMP2B and LAMP-2C with identical luminal regions but different transmembrane and cytosolic tails. Substrate binding to the LAMP-2A cytosolic tail does not occur at the KFERQ-targeting region and a designated LAMP-2A-binding motif in the substrate has not been identified yet. However, the fact that substrate binding requires the four positive charges in the LAMP-2A cytosolic tail suggests that electrostatic interactions, rather than specific amino acid residues, mediate substrate binding.
The function of LAMP-2A extends beyond that of a receptor as this protein is also an essential component of the CMA translocation complex (Bandyopadhyay et al., 2008). Binding of substrate proteins to LAMP-2A monomers drives its organization into a 700 kDamultimeric complex at the lysosomal membrane. The motif present in the transmembrane region of LAMP-2A is important for multimerization. We have shown
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that mutations that prevent multimerization abolish substrate translocation but not substrate binding to LAMP-2A (Bandyopadhyay et al., 2008).
Although, in contrast to other translocation systems, luminal chaperones do not form part of a stable translocon unit in CMA, they are still essential for substrate uptake. In fact, a form of hsc70 resident in the lysosomal lumen is needed for complete translocation of substrate proteins into lysosomes. Incubation of cultured fibroblasts with blocking antibodies against hsc70 that reach the lysosomal lumen through endocytosis exerts a strong inhibitor effect on CMA. Furthermore, levels of lys-hsc70 have helped identify subgroups of lysosomes that manifest different ability to perform CMA. Only those lysosomes containing hsc70 in their lumen are competent for uptake of CMA substrates. Interestingly, the percentage of hsc70-containing lysosomes, which is no more than 40% under resting conditions, escalates to 80% in liver under conditions in which CMA is up-regulated, such as during prolonged starvation or mild oxidative stress. This increase in the amount of lysosomes competent for CMA is a consequence, at least in part, of changes in the luminal acidification in these organelles. Thus, lyshsc70 is stable in the lysosomal lumen at a pH of around 5.2, but a slight increase in the lysosomal pH is enough to destabilize this protein and make it amenable to degradation by the abundant lysosomal protease. Many factors could contribute to transient changes in lysosomal pH and the subsequent destabilization of hsc70. Among them, we have recently identified that fusion of lysosomes with autophagosomes when
macroautophagy is maximally activated contributes to a dissipation of pH enough to
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render hsc70 unstable, and results in decreased CMA activity. The pH dependence of lys-hsc70 may thus constitute a novel regulatory node in the cross-talk between macroautophagy and CMA.
The study of CMA in particular cell types and the characterization of the degradation of specific cellular proteins by CMA are behind the cell typespecific functions recently proposed for this pathway. CMA activity has been linked to the regulation of cellular proliferation in tubular kidney cells through the degradation of Pax2. Levels of this transcription factor, an essential regulator of kidney cell proliferation and differentiation, are controlled through its degradation by CMA. Consequently, changes in CMA activity may modulate kidney organogenesis and growth. Similarly, a role for CMA in antigen presentation has been proposed in dendritic cells. Macroautophagy has been shown to contribute to both the presentation of endogenous peptides on major histocompatibility complex class II molecules, as well as the presentation mediated by MHC class I molecules. Although relatively limited information is available on the contribution of CMA to immunity, recent studies have shown that reduction of LAMP-2A or hsc70 levels decreases presentation via MHC class II. Interestingly, pharmacological inhibition of hsp90, which will reduce CMA activity, also resulted in decreased antigen presentation in a second independent study. Antigen processing and loading usually occurs in endosomes rather than in secondary lysosomes, as the lower proteolytic capacity of the former compartment allows preservation of the presenting peptides and their loading on MHC class II molecules.
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However, to date, CMA has only been described to take place in secondary lysosomes. Future studies are required to determine whether this hsc70-mediated presentation of antigens takes place in late endosomes or in lysosomes.
Lysosomal storage disorders (LSDs) are a group of genetic diseases resulting from loss of a specific lysosomal enzyme activity, and the consequent accumulation of its substrates in the lysosomal compartment. The enzymatic impairment can result from the malfunctioning of a specific enzyme in lysosomes, or from failure in its delivery to this compartment. CMA, like any other type of autophagy, is likely to be indirectly affected in these pathologies, because lysosomes are the final compartment for all autophagic pathways. However, a direct connection to CMA has been recently established with two different LSDs which includesgalactosialidosis and mucolipidosis type IV. Patients with galactosialidosis lack cathepsin A, a protein that acts as chaperone for different lysosomal enzymes, but that has also been recently shown to participate in LAMP-2A turnover. The inability to properly degrade LAMP-2A in the cells from these patients results in abnormally high rates of CMA. In the case of patients with mucolipidosis type IV, who bear a mutation in the transient receptor potential mucolipin1, CMA activity decreases. The fact that hsc70 interacts with this receptor has led to the proposition that altered docking of hsc70 at the lysosomal membrane could be behind the observed decrease in CMA. However, another possible explanation that requires further testing is that the small molecule channeling activity of this membrane protein is required for CMA.
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Although the classification as LSD has been traditionally restricted to defects in enzymatic activity, recently, alterations in nonenzymaticlysosomal proteins, such as membrane proteins, have also been shown to result in lysosome malfunctioning and substrate accumulation. Among these new forms of LSD, of particular relevance for CMA is Danon disease, a vacuolar myopathy that originates from a primary defect in the lamp2 gene. Although, as indicated in previous sections, elimination of the three protein variants of this gene will result in a complex phenotype, it is anticipated that patients with Danon disease will also have reduced CMA activity.
Chaperone-Mediated Autophagy in Cancer Biology Autophagy plays a crucial role in maintaining neuronal homeostasis through clearance of defective organelles and unfolded/aggregating proteins. Knockout of autophagy pathway genes leads to accumulation of poly-ubiquitinated protein aggregates and can result in neurodegeneration, and motor and behavioral deficits in mice. Also, autophagy interacts with other protein degradationand vesicular trafficking pathways. While autophagy can at least partially substitute for reduced proteasomal activity and vice versa, the disturbance of the endosomal-lysosomal system disrupts autophagy and reduced autophagy impairs endosomal-lysosomal trafficking. It clears neurotoxic proteins. The activation of this reduces the toxicity of aggregation prone proteins, while inhibition of autophagy impairs their clearance and causes enhanced cellular stress and neurodegeneration. This can also be a cellular death pathway, which
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isactivated in neurons after acute injury and inhibition of autophagy under those conditions can reduce neurodegeneration. However, autophagy is impaired in the final stages of most neurodegenerative diseases.
Numerous observations suggest the existence of strong links between autophagy and cancer. Several tumor suppressor genes stimulate autophagy, whereas oncogenes are known that inhibit autophagy. The connection between both processes is probably related to the overlap that exists between the pathways involved in regulation of autophagy and tumorigenesis. Mutations that affect the function of mTOR or Beclin 1 have been identified in human cancers (Cao, 2007).The function of mTOR overlaps with signaling pathways involved in tumorgenesis. Several tumor suppressor genes have been shown being involved in the upstream inhibition of mTOR signaling and in this way stimulate autophagy. Moreover, oncogene proteins are known that activate mTOR. The importance of Beclin 1 in human cancers is illustrated by the fact that mono-allelic deletions in Beclin 1 occur in a 40 75 % of cases of human breast, ovarian and prostate cancer. Whether this only relates to the function of Beclin 1 in autophagy or also to autophagy-independent functions of Beclin1 is not yet known (Cecconi and Levine, 2008).
Selectively inhibited CMA by knocking down the LAMP-2A lysosomal receptor in cultured cancer cell lines and in mice carrying human primary lung tumor xenograft s using short hairpin RNAs (shRNAs). Although such an approach is the best available
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method to impair CMA in tumor cells, it does raise an important cave at as it is formally possible that LAMP-2A may possess additional functions that are separate from its role in CMA. Nonetheless, even bearing this in mind, the results here are provocative because they demonstrate that impaired CMA is sufficient to reduce tumor cell proliferation rates both in vitro and in vivo. These effects are CMA-specific because knockdown of a gene that is essential for macroautophagy (atg7) had little effect on tumor growth. Inhibition of the CMA pathway also reduces the metastatic potential of the tumor cells, which is extremely important from a clinical perspective given that metastatic disease remains the principal cause of cancer mortality. In the real world, most treatment is targeted to patients presenting with established cancers (Kon et al., 2011) to ask whether an established tumor is affected when CMA is blocked by viral delivery of shRNAs that target LAMP-2A. They found that the direct injection of
lentivirus encoding LAMP-2A shRNAs into tumor xenogra s caused marked regression that was associated with increased tumor cell death as well as reduced staining for Ki67, which is a standard marker for tumor cell proliferation. Thus, it appears that CMA is required for optimal tumor growth and metastasis to distant sites and that targeting CMA in established tumors can induce the tumor cells to slow their growth and undergo apoptosis leading to tumor regression. How does blockade of the CMA pathway elicit such profound antitumor phenotypes. At least part of the explanation is related to changes in cellular metabolism in CMA-defi cient cancer cells. Bioenergetic assays indicated that inhibiting CMA produced a decrease in the glucosedependent extracellular acidifi cation rate (ECAR), a finding consistent with
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reduced glycolysis. In contrast, no changes in oxygen consumption or oxidative metabolism were eadily evident in the CMA-deficient cancer cells. Increased aerobic glycolysis is a well-known characteristic of tumor cells, commonly termed the Warburg effect; moreover, abundant data indicate that reduced glycolytic metabolism, such as observed here are CMA blockade, can profoundly attenuate both energy (adenosine triphosphate) production and biosynthetic capacity, which are vital for cancer cell growth and proliferation. Notably, this reduction in glycolysis in CMA-decient cancer cells was associated with a decrease in several glycolytic enzymes. This result is somewhat counterintuitive because these glycolytic enzymes possess KFERQ motifs and are known substrates for CMA-mediated degradation; as a result, one would expect that blocking CMA should result in an increase in these glycolytic enzymes, rather than the decrease observed. The authors propose that this decrease might be at least partly due to activation of the tumor suppressor p53 in CMA-defi cient cells, which results in the transcriptional downregulation of multiple glycolytic enzymes. Nonetheless, because CMA activity is upregulated in cancer cells independent of their p53 status, it is very likely that CMA deficiency inhibits tumorigenesis by other mechanisms in addition to p53-mediated suppression of glycolysis. One of the main mechanisms by which macroautophagy potentially suppresses tumor development is by eliminating stress-related molecules, such as p62/SQSTM1, as well as oxidized, damaged proteins (Matthew, etal. 2009 ). This does not seem to apply to CMA because there were no apparent differences in p62/SQSTM1 protein levels and no increases in oxidized or aggregated proteins when the CMA pathway was
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inhibited. Notably, the authors demonstrate that CMAdeficient cancer cells display a compensatory increase in proteasomal degradation of CMA protein substrates, which appears to be critical for maintaining protein quality control and mitigating the effects of oxidative stress. Second, are the mechanisms underlying the antitumor effects of CMA inhibition similar to those underlying the effects of macroautophagy inhibition. Despite the compensatory increase in proteasomal degradation, an intriguing possibility is that there is accumulation of specific target proteins containing the KFERQ motif, resulting in the phenotypic changes observed in cells with a defective CMA pathway. In principle, approximately one-third of the proteome can be targeted for CMA-mediated degradation because about 30% of proteins contain the hsc70-targeting sequence (Arias and Cuervo, 2011). However, the number of definitively identified CMA substrates is much smaller than this. Hence, if currently unknown CMA substrates do indeed exist in cancer cells, identifying these molecules will be key to understanding the precise mechanisms through which CMA is mediating tumor development.
Most important of all, how do these findings relate to better treatments for cancer, The data presented in the Kon et al. paper suggest that CMA inhibitors could be useful for cancer therapy, as they should inhibit tumor growth and also reduce the ability of tumor cells to metastasize. From a therapeutic standpoint, an important limitation is that we do not currently have a feasible method to selectively inhibit CMA in patients (unlike in the mouse xenograft model). Thus, we are unable to reliably reduce LAMP-2A protein concentrations within tumor cells in people and, to date, we lack pharmacological
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inhibitors that selectively block the CMA pathway. We do, however, have drugs that more broadly inhibit all forms of lysosomal degradation. The most widely used of these include chloroquine and hydroxychloroquine, which are being tested in a number of clinical trials (more than 30 such trials are currently listed on the ClinicalTrials.gov Web site) in combination with other anticancer drugs (Aramavadi, etal., 2011). The rationale behind these trials is to block macroautophagy, but the question is whether CMA will also be inhibited in these patients. Therefore, should there be any beneficial results from these trials, we would need to consider whether it is CMA rather than macroautophagy that is the critical target of chloroquine or hydroxychloroquine. Last, but not least, like all anticancer strategies, it seems unlikely that all tumors will respond equally well to CMA inhibition. Therefore, it will be critical to identify markers that predict the dependence of tumors on CMA before blocking this pathway. In this regard, the interconnections between macroautophagy and CMA will be important to uncover. Remarkably, when tumor cells are transformed due to mutation of the small GTPase Ras, this leads to a requirement for macroautophagy that has been proposed to facilitate glycolysis (Lock, etal., 2011). Similarly, it has been suggested that the presence of oncogenic Ras mutations makes tumor cells addicted to
(macro)autophagy (Guo, 2011). Accordingly, tumor types in which Ras mutations are particularly common, such as pancreatic cancer, have been found to be particularly sensitive to growth inhibition by chloroquine (Yang, 2011). These studies point to
specific patient subsets, such as those with tumors harboring Ras mutations, where inhibition of macroautophagy may be particularly useful. Interestingly, several of the
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lung cancer cell lines used by Kon et al. possess K-Ras mutations, immediately raising the question of whether Ras-transformed cells are similarly addicted to CMA and
whether CMA inhibition, rather than macroautophagy inhibition, dictates the response to chloroquine observed in the aforementioned studies. The answers to these and the many other questions that arise from the exciting new study of Kon et al. will no doubt keep cancer investigators working on autophagy very busy. However, what seems clear is that it is unwise for cancer biologists to exclusively focus on macroautophagy in tumor cells at the expense of CMA. If we continue to do so, we are certain to overlook some of the most important aspects of autophagy in cancer biology.
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Literature Cited
Alison, Malcolm R. Cancer. Encyclopedia of Life Sciences. Imperial College School of Medicine, London, UK. 2001. Web. 05 Mar. 2012. Auyang, Sunny Y. Cancer Causes and Cancer Research on Many Levels of Complexity. http://www.creatingtechnology.org/biomed/cancer.pdf. 05 Mar. 2012. Beau, I.,Codogno, P., Esclatine, A., Mehrpour, M. 2010. Autophagy in health and disease: Regulation and significance of autophagy: an overview. Clapp, Richard D.Sc., Genevieve Howe, MPH and Molly Jacobs Lefevre, MPH. Environmental and Occupational Causes of Cancer: A Review of Recent Scientific Literature. Boston University School of Public Health. 2005. Web. 05 Mar. 2012. Cuervo, A. M ., Bejarano, E. 2010.Chaperone-Mediated Autophagy. Cuervo, A. M., Wong, E., Orenstein, S., Vicente, M-M., Kiffin, R., Sridhar, S., Bandyopadhyay, U., Kaushik, S. 2011. Chaperone-mediated autophagy at a glance. Lam, Michael M.D. Beating Cancer with Natural Medicine. Bloomington, IN. United States of America. 2003. Web. 05 Mar. 2012. Qian, Y., Mao, Z. 2009. Regulation of MEF2s by chaperone-mediated autophagy. Departments of Pharmacology and Neurology; Emory University School of Medicine; Atlanta, Georgia USA. Rath, Matthias M.D. Cellular Health Series Cancer. MR Publishing, Inc., Santa Clara. 2001. Web. 05 Mar. 2012.
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POLYTECHNIC UNIVERSITY OF THE PHILIPPINES COLLEGE OF SCIENCE DEPARTMENT OF BIOLOGY

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

macroautophagy is maximally activated contributes to a dissipation of pH enough to

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

Chaperon-Mediated Autophagy in Cancer Biology

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