Abstract #SY21-3: Tumor suppression by autophagy and therapeutic implications

Autophagy is a cellular response to starvation and stress where cellular components such as organelles, protein aggregates and cytoplasm are captured in vesicles called autopagosomes, which fuse with lysosomes where the cargo is degraded (1). This lysosome-mediated degradation of intracellular components through autophagy serves multiple purposes including sustaining cellular energy homeostasis during starvation through recycling of cellular components, and damage mitigation and host defense though the clearance of damaged proteins, organelles and intracellular pathogens. Defects in autophagy have been implicated in many diseases including neurodegenerative diseases, ageing, liver disease, and Crohn\#8217;s and other diseases associated with defective regulation of innate immunity. Importantly, autophagy plays multiple roles in cancer, which are only now being realized. Autophagy is activated by hypoxia and metabolic stress in tumors and localizes to metabolically stressed tumor regions where it enables tumor cell survival, suggesting that the enhanced stress tolerance provided by autophagy may facilitate tumor growth (2-4). Autophagy may enable tumor cell survival to metabolic stress through sustaining energy homeostasis and through damage mitigation by degrading damaged proteins and organelles that accumulate during stress (2-4). These findings support the possibility of using autophagy inhibitors for cancer therapy to eradicate stressed tumor cells surviving by autophagy in hypoxic tumor regions (5). As with metabolic stress, most targeted and cytotoxic chemotherapeutics induce autophagy, and whether this supports tumor cell survival and impairs treatment response needs to be established. In particular, mTOR inhibitors activate autophagy, and whether the activity of these promising agents can be improved with autophagy inhibitors will be of great interest. If so, combining autophagy inhibitors with both targeted and cytotoxic chemotherapeutics that induce autophagy will be advantageous. In preclinical models, inhibition of autophagy with hydroxychloroquine synergizes with chemotherapy and suppresses tumorigenesis (6, 7), and clinical trials to test the value of combining autophagy inhibition with chemotherapy in cancer patients are ongoing. Thus, in established tumors pharmacologic inhibition of autophagy may be therapeutically beneficial. Many cancers have autophagy suppressed, either through allelic loss of the essential autophagy gene beclin1 or through constitutive activation of the PI-3 kinase pathway, which activates mTOR that suppresses autophagy (1, 5). Indeed, allelic loss of beclin1 renders mice tumor prone, supporting a role for autophagy in tumor suppression, the mechanism of which is beginning to emerge. Autophagy suppresses cell death and inflammation as one possible mechanism of tumor suppression (2). The damage mitigation function of autophagy, particularly suppression of genome damage and chromosome instability, may also contribute to tumor suppression by reducing the mutation rate of tumor cells (3, 4). How autophagy mitigates cellular damage is not entirely clear, but clearance of damaged proteins and organelles and suppression of oxidative stress is a likely possibility. In some cases, progressive or over-stimulation of autophagy leading to cell death through cellular self-consumption has been proposed as a tumor suppression mechanism, but physiological situations demonstrating this in cancer have so far been lacking (8). Nonetheless, these findings suggest that stimulation of autophagy may have value for cancer chemoprevention. Tumors have differing capacities for autophagy, suggesting that modulating autophagy in cancer therapy may benefit from knowing the inherent capacity of tumors for autophagy. Identification of molecular signatures and biomarkers that reflect the functional status of autophagy in human cancers will be important to guide deployment of autophagy modulators in cancer therapy. In addition to allelic loss of beclin1 and constitutive activation of the PI-3 kinase pathway that suppress autophagy, other notorious oncogenic pathways functionally intersect with autophagy regulation. Defects in apoptosis allow sustained survival by autophagy (2, 9) yet the anti-apoptotic protein Bcl-2 binds Beclin1 and can suppress autophagy, suggesting crosstalk between the apoptosis and autophagy pathways (10). The p53 tumor suppressor protein activates autophagy (11), as does the loss of p53 (12), suggesting that autophagy may be a component of the p53 tumor suppression mechanism, but also that cellular stress associated with the absence of the p53 checkpoint can induce autophagy. Thus many critical oncogenic pathways modulate autophagy and the consequences to cancer initiation and progression and to therapeutic response need to be established. It is clear that defining the role and regulation of autophagy in tumorigenesis and in treatment response is a new and important area. Moving forward, it will be important to establish the functional consequence of the autophagic response in cancer treatment and then modulate autophagy accordingly for therapeutic benefit. Defining the mechanisms involved in autophagy regulation will be essential for the optimum deployment of current anti-cancer therapeutics and for the development of novel therapies targeting the autophagy pathway. 1.%9Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008;132:27-42. 2.%9Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006;10:51-64. 3.%9Karantza-Wadsworth V, Patel S, Kravchuk O, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007;21:1621-35. 4.%9Mathew R, Kongara S, Beaudoin B, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007;21:1367-81. 5.%9Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer 2007;7:961-7. 6.%9Amaravadi RK, Yu D, Lum JJ, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007;117:326-36. 7.%9Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest 2008;118:79-88. 8.%9Kroemer G, Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 2008;9:1004-10. 9.%9Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 2005;120:237-48. 10.%9Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005;122:927-39. 11.%9Crighton D, Wilkinson S, O'Prey J, et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 2006;126:121-34. 12.%9Tasdemir E, Maiuri MC, Galluzzi L, et al. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 2008;10:676-87.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY21-3.