Chaperone-mediated autophagy and cancer
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Chaperone-mediated autophagy (CMA) is one of the three autophagic pathways described in mammals, which has been shown to be an important component of the cellular response to stress, along with another autophagic pathway - macroautophagy. Malfunctioning of both processes has been implicated in several pathologies. In particular, macroautophagy has a dual pro- or anti-oncogenic role in cancer but the role of CMA has yet to be defined in both tumorigenesis and in the cellular response to anti-cancer treatments.;We hypothesized that CMA, being an important homeostatic and stress-response mechanism, could have a role in cancer cell survival and may be regulated by proteins that are involved in tumorigenesis. We show that CMA is consistently upregulated in most cancer cell lines and in primary human tumors of different organ origin. We inhibited CMA activity in two different human lung cancer cell lines and found that this manipulation leads to decreased in vitro cellular proliferation, clonigenicity, motility, as well as to changes in glucose and lipid metabolism. In vivo, cells with compromised CMA formed smaller xenografts in mice and a marked lower number of lung metastasis. Inhibition of CMA in already formed xenografts lead to tumor shrinkage as a result of reduced proliferation and increased cellular death. These findings suggest a promising potential for CMA manipulation as the basis for the future development of anti-cancer treatment.;We also investigated a potential role for p53 in regulating CMA. We found that p53 is able to stimulate CMA activity in physiological conditions, as well as during stress situations, such as starvation, oxidative and ER stress. Interestingly, we discovered that a subset of cytosolic p53 is recruited to lysosomes under these circumstances and can directly stimulate CMA in partnership with cytosolic chaperones, such as hsc70 and hsp90 This new regulatory role of p53 on CMA could be an important addition to the expanding list of the roles of p53 in physiological conditions.;Our studies establish for the first time a connection between CMA and cancer biology, and reveal that modulation of this cellular process could have important implications in future development of anticancer treatments.
- Theses and Dissertations