EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 44, No. 2, 109-120, February 2012 Autophagy and cancer Kyeong Sook Choi1 Department of Molecular Science and Technology Institute for Medical Sciences Ajou University School of Medicine Suwon 443-721, Korea 1Corresponding author: Tel, 82-31-219-4552; Fax, 82-31-219-4530; E-mail, kschoi@ajou.ac.kr http://dx.doi.org/10.3858/emm.2012.44.2.033 Accepted 5 January 2012 Available Online 19 January 2012 Abbreviations: 3-MA, 3-methyladenine; AMBRA1, activating molecule in Beclin-1-regulated autophagy protein 1; AMPK, 5' AMP-activated protein kinase or AMP-activated protein kinase; ATG, autophagy- related gene; BFA, bafilomycin A1; CQ, chloroquine; DAPkinase, death associated protein (DAP) kinase; EGCG, epigallocatechin- 3-gallate; HCQ, hydroxychloroquine; HDAC inhibitor, histone deacetylases inhibitor; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homolog; RNAi, RNA interference; TSC, tuberous sclerosis complex Abstract Basal autophagy plays a critical role in maintaining cel- lular homeostasis and genomic integrity by degrading aged or malfunctioning organelles and damaged or misfolded proteins. However, autophagy also plays a complicated role in tumorigenesis and treatment responsiveness. It can be tumor-suppressing during the early stages of tumorigenesis (i.e., it is an anti-tu- mor mechanism), as reduced autophagy is found in tu- mor cells and may be associated with malignant transformation. In this case, induction of autophagy would seem to be beneficial for cancer prevention. In established tumors, however, autophagy can be tu- mor-promoting (i.e., it is a pro-tumor mechanism), and cancer cells can use enhanced autophagy to survive under metabolic and therapeutic stress. The pharma- cological and/or genetic inhibition of autophagy was recently shown to sensitize cancer cells to the lethal ef- fects of various cancer therapies, including chemo- therapy, radiotherapy and targeted therapies, sug- gesting that suppression of the autophagic pathway may represent a valuable sensitizing strategy for can- cer treatments. In contrast, excessive stimulation of autophagy may also provide a therapeutic strategy for treating resistant cancer cells having high apoptotic thresholds. In order for us to develop successful au- tophagy-modulating strategies against cancer, we need to better understand how the roles of autophagy differ depending on the tumor stage, cell type and/or genetic factors, and we need to determine how specific pathways of autophagy are activated or inhibited by the various anti-cancer therapies. Keywords: autophagy; cell death; cell transformation, neoplastic; neoplasms; therapeutics Introduction Autophagy is a self-digestive process that ensures the lysosomal degradation of superfluous or damaged organelles and misfolded proteins (Levine and Klionsky, 2004). Basal autophagy helps maintain homeostasis by contributing to protein and organelle turnover, while additional autophagy is induced in stressed cells as a cell-survival mechanism. Autophagic defects have been implicated in various diseases and health states, including neurodegeneration, aging, infection, myopathy, Crohn's disease and cancer (Levine and Kroemer, 2008). However, the role of autophagy in cancer is quite complicated and still somewhat controversial; it appears to be tumor suppressive during cancer development, but contributes to tumor cell survival during cancer progression (Rouschop and Wouters, 2009). Furthermore, tumor cells can use autophagy to resist various anti-cancer therapies (Chen and Karantza-Wadsworth, 2009). Cancer cells experience higher metabolic demands and stresses than normal cells, due to their rapid proliferation and altered glycolytic metabolism (White and DiPaola, 2009), and thus may depend more heavily on autophagy for survival (Amaravadi et al., 2011). In many experimental settings, the inhibition of autophagy has been shown to enhance the therapeutic benefits of various cancer therapies (Chen and Karantza-Wadsworth, 2009; Chen et al., 2010). However, strategies to induce autophagic cell death have also shown promise as a means for killing certain types of cancer cells with high Copyright ⓒ 2012 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.