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  • br Autophagy removes oncogenic proteins and maintains genomi


    3.1.1. Autophagy removes oncogenic proteins and maintains genomic stability
    p53 is activated in response to a variety of stress conditions, in-cluding DNA damage, oxidative stress, replicative stress, genomic in-stability etc. (Meek, 2015). In cancer cells, the proteasomal degradation of the mutant p53 protein was abolished but instead it was degraded by autophagy. Indeed, glucose deprivation induced autophagy and regu-lated acetylation of the mutant p53 that subsequently led the autop-hagic clearance of protein (Rodriguez et al., 2012). Correlating with anti-tumor effect of autophagy on p53, in another study it has been shown that an anti-tumor agent selenite induced ROS and inhibited autophagy in NB4 FilipinIII (Shi et al., 2014). Furthermore, the same group also showed that selenite-induced ROS regulated autophagic activity through downregulation of ULK1 expression was also affected by phosphorylation status of p53. In fact, p70S6K-mediated phosphoryla-tion of p53 was responsible for the decreased level of ULK1 which was attenuated with selenite (Ci et al., 2014). Moreover, it has been also showed that chaperone-mediated autophagy (CMA) could degrade mutant form of p53 in nonproliferating tumor cells under the conditions in which autophagy and proteasomal degradation is inhibited (Vakifahmetoglu-Norberg et al., 2013). Additionally, autophagy was also contributed to the p53-mediated senescence through degradation of inhibitory isoforms of p53 (Horikawa et al., 2014). On the other hand, Beclin-1 was also involved in the autophagic control of cellular p53 level. An inhibitor of autophagy, Spautin-1 deregulated the for-mation of VPS34 complex acting over the two ubiquitin-specific pep-tidases USP10 and USP13 that modifies Beclin-1 ubiquitylation pattern. Hence, USP10 also regulates p53 ubiquitylation status and is re-sponsible for the p53 stability, Spautin-1-mediated autophagy  European Journal of Pharmaceutical Sciences 134 (2019) 116–137
    inhibition led to degradation of p53 (Liu et al., 2011). Furthermore, it has been also observed that Beclin-1 interacted with p53 through its BH3 domain and this interaction was critical for its UPS-mediated de-gradation. Degradation of Beclin-1 subsequently decreased autophagic activity and have effect on the determination of embryonal carcinoma cellular fate (Tripathi et al., 2014).
    The first identified autophagy receptor protein p62 (also known as sequestosome-1, SQSTM1) is a signaling scaffold within the cytoplasm and its expression is generally upregulated in human cancers (Moscat et al., 2007). Target selectivity by p62 during selective and non-selec-tive autophagy governs cellular homeostasis by preventing ER-stress and oxidative stress (Moscat et al., 2016). The critical role of p62 in tumorigenesis was explored in different types of cancer such as pre-malignant liver diseases as well as hepatocellular carcinoma (HCC). In autophagy deficient cases, p62 was shown to be associated with the formation of benign adenomas (Takamura et al., 2011). Diethylni-trosamine (DEN) induced carcinogenic activity of p62 and accelerated HCC progression (Umemura et al., 2016). Critical tumor promoting role of p62 in HCC occurred over NRF2 and mTORC1/c-Myc signaling (Umemura et al., 2016). Therefore, degradation of p62 during autop-hagy is critical for the restriction of p62-linked tumorigenesis.
    Promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARA) is a critical fusion oncoprotein responsible for the progression of acute PML (Grignani et al., 1998). It has been discovered that PML-RARA was degraded by autophagy (Isakson et al., 2010). PML-RARA-targeting drugs such as retinoic acid and arsenic trioxide (Zhu et al., 2001) also induced cellular autophagy level suggesting that the effect of these drugs on oncoproteins is autophagy-dependent (Isakson et al., 2010). In line with this, another critical oncogenic protein BCR-ABL1 involved in leukemia found to be degraded by autophagy (Goussetis et al., 2012). Arsenic trioxide enhanced both cellular autophagic activity and the degradation of BCR-ABL1 which was reversed with autophagy in-hibitors (Goussetis et al., 2012). Furthermore, the physical interaction between p62 receptor and BCR-ABL1 could be associated with selective removal of the oncoproteins supporting the repressive role of autop-hagy in tumorigenesis.
    3.1.2. Autophagy regulates cell proliferation and promotes death mechanisms
    Programmed cell death (PCD) mechanisms including apoptosis, necroptosis and autophagy are among the first line barriers, which prevent survival and proliferation of malignant cells (Kroemer and
    Fig. 2. Tumor suppressor role of autophagy.