110 Exp. Mol. Med. Vol. 44(2), 109-120, 2012 Figure 1. Oncogenes and tumor suppressors associated with the regulation of autophagy. Tumor suppressors (blue) except for cytoplasmic p53 are among the factors positively regulating autophagy, whereas oncogene products (pink) inhibit autophagy. Growth factor signaling activates the PI3K/Akt/mTOR axis resulting in autophagy inhibition. In contrast, class III PI3K activates autophagy. Low cellular energy levels with increased AMP/ATP ratio activate the LKB1-AMPK-mTOR pathway to also upregulate autophagy. p53 exhibits complex autophagy regulation, as nuclear p53 activated by genotoxic or oncogenic stress positively regulates autophagy by inhibiting mTOR in an activated AMPK- and TSC1/TSC2-dependent manner, whereas cytoplasmic p53 can suppress autophagy. apoptotic thresholds (Gozuacik and Kimchi, 2007). Although we still have much to learn about the regulation of autophagy in cancer, it appears to provide a promising target for cancer treatment. This review examines the multiple roles of auto- phagy as a novel target for anticancer therapy and assesses the current efforts and remaining tasks in the development of autophagy-modulating strategies against cancer. Roles of autophagy in cancer Autophagy as a tumor-suppressing mechanism Deficiencies in autophagy lead to the accumulation of damaged macromolecules and organelles (particularly mitochondria), subsequently inducing oxidative stress, DNA damage and chromatin instability (Levin and Klionsky, 2004; Chen and Karantza, 2011). Thus, autophagic defects are ultimately associated with the accumulation of oncogenic mutations and increased tumor susceptibility (Karanta-Wadsworth et al., 2007; Mathew et al., 2007). Some of the most important evidence for the role of autophagy in tumor suppression comes from studies on the Bcl-2-interacting protein, Beclin 1 (BECN1, also called ATG6). For example, mono- allelic deletion of Beclin 1 has been frequently observed in human breast (Futreal et al., 1992), ovarian (Aita et al., 1999) and prostate cancers (Gao et al., 1995), and mice with a disrupted Beclin 1 gene had a higher incidence of lymphoma, lung cancer and liver cancer (Qu et al., 2003; Yue et al., 2003). Constitutive activation of the PI3K-Akt-mTOR axis, a common characteristic of cancer (LoPiccolo et al., 2008), is known to suppress autophagy (Janku et al., 2011), while promoting tumor cell growth, proliferation and survival (Martelli et al., 2007) (Figure 1). A number of tumor suppressor proteins have been shown to promote autophagy, including Atg4c (Mariño et al., 2007), Bax- interacting factor-1 (Bif-1) (Takahashi et al., 2007), BH3-only proteins (Maiuri et al., 2007), DAPkinase (Bialik and Kimchi, 2010), LKB1 (Liang et al., 2007), ultraviolet radiation resistance-associated gene (UVRAG) (Liang et al., 2006), PTEN (Arico et al., 2001), TSC (Zhou et al., 2009), nuclear p53 (Maiuri et al., 2010) and AMPK (Luo et al., 2010). Furthermore, autophagy has been shown to reduce intratumoral necrosis and local inflammation (Degenhardt et al., 2006). Collectively, these results support the contention that autophagy plays a tumor-suppressing role in cancer, and suggest that reduced autophagic activity may constitute a hallmark of cancer (Hanahan and Weinberg, 2011). Autophagy as a pro-survival and resistance mechanism In established cancer cells, metabolic stress (which arises as a result of insufficient nutrient or oxygen supplies and/or the increased energetic demands