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  • br Accumulating evidences suggest that autophagy promote tum


    Accumulating evidences suggest that autophagy promote tumor cell survival in majority of the tumors that grow under hypoxic conditions (Vaupel and Mayer, 2007). Insufficient supply of oxygen from the vasculature to the solid tumor mass resulted in local hypoxic (oxygen < 3%) and anoxic (oxygen < 0.1%) conditions inside the tumor. Compromised microvessel function, limited oxygen diffusion rate due to increased and condensed structure of tumor induced hy-poxic conditions inside the tumor tissue (Qiu et al., 2017). Hypoxia-induced autophagy mainly depends on hypoxia-inducible factors (HIFs), a family of proteins predominantly detected when oxygen level is below 5% (Majmundar et al., 2010). HIF-1α activation further pro-moted autophagy through BNIP3 and BNIP3L under hypoxic condi-tions. The atypical BH3 domains of these proteins have been proposed to induce autophagy by disrupting the BCL-2-Beclin-1 complex without inducing cell death (Majmundar et al., 2010). Therefore, this me-chanism is considered as a survival mechanism promoting tumor pro-gression (Zhang and Ney, 2009).
    HIF-1α and HIF-2α are targeted to proteosomal degradation by the E3 ubiquitin protein ligase VHL in an oxygen-dependent reaction are stabilized in hypoxic conditions (Majmundar et al., 2010). The HIF are also implicated in increased Cefepime metabolic flux and survival through upregulation of GLUT1 and glycolytic enzymes (Altman and Rathmell, 2012; Chen et al., 2001). Interestingly, various VHL muta-tions in renal cell carcinomas (Shuin et al., 1994) led to accumulation of HIF-1α irrespective of oxygen concentration and transactivation of genes involved in bioenergetic metabolism and angiogenesis (Maxwell et al., 1999). VHL inhibited autophagy through MIR204 upregulation, which directly targets LC3B in renal clear cell carcinoma (Mikhaylova et al., 2012). On the other hand, knockdown of LC3C in VHL-expressing cells could successfully induce tumor formation (Von Muhlinen et al., 2013). Additionally, through inhibition of HIF, VHL induced LC3C ex-pression possessing tumor-suppressing autophagic activity (Galluzzi et al., 2015; Von Muhlinen et al., 2013).
    BNIP3 and BNIP3L protein levels were also under the control of FOXO3 transcription factor that induced autophagy (Mammucari et al., 2007). Interestingly, FOXO3A-mediated activation of autophagy was also shown to promote survival of hematopoietic stem cells under nu-trient-deprived conditions (Warr et al., 2013). BNIP3L, is often found on the outer mitochondrial membrane, modulating elimination of mi-tochondria by autophagy (mitophagy) (Zhang and Ney, 2009). As well  European Journal of Pharmaceutical Sciences 134 (2019) 116–137
    as taking a part in the turnover of dysfunctional mitochondria by mi-tophagy also promoted reduction of overall mitochondrial mass in re-sponse to hypoxia and nutrient starvation. Removal of mitochondria under unfavorable conditions helped reducing ROS production, saved oxygen and nutrients from being consumed inefficiently, thereby pro-moting cellular survival under hypoxic conditions (Chourasia et al., 2015). The expression level of the essential autophagy genes LC3 and ATG5 was found to be upregulated through the transcription factors ATF4 and CHOP, which are regulated by PERK (Rouschop et al., 2010). In this context, inhibition of autophagy sensitized human tumor cells to hypoxia suggesting that autophagy had a role in tumor survival under hypoxic conditions.
    Reactive oxygen (ROS) and reactive nitrogen species (RNS) are one of the major sources of DNA damage (Wiseman and Halliwell, 1996). ROS and RNS modify nucleic acids directly or indirectly generating different types of DNA lesions including single-strand break (SSB), double-strand break (DSB), oxidized bases, abasic sites, and DNA–pro-tein crosslinks (Cooke et al., 2003). ROS and RNS are also contributed to damage in mitochondrial DNA (mtDNA) integrity and function. For example, damaged mtDNA affected the transcription of mtDNA-coded proteins and RNAs that function in the mitochondrial respiratory chain (except Complex II) (Roos et al., 2013). Then, damaged mtDNA induces accumulation of more dysfunctional mitochondria, which produce a high rate of ROS, leading to further mitochondrial impairment and cell death (Filomeni et al., 2015). In fact, this effect further enhanced in majority of the cancers carrying p53 deletions due to the lack of ability to repair DNA damage efficiently. The expression of autophagy-related genes was also regulated in a p53-dependent manner in response to DNA damage. These include both upstream regulators of autophagy (e.g., PTEN, TSC2, β1, β2 and γ subunits of AMPK) and the proteins that are involved in autophagosome formation (e.g., ULK1, UVRAG, ATG2, 4, 7, 10) (Füllgrabe et al., 2016). Although, DNA damage promote tu-morigenesis at a certain degree, due to the accumulation of oncogenic mutations, excessive DNA damage also caused cell death. Therefore, based on the well-established role of autophagy in intracellular home-ostasis and its functions in DNA damage response, autophagy also plays a key role in protecting cancer cells from the lethal effects of DNA damage (Chan et al., 2018).