br Another link between autophagy cell proliferation
Another link between autophagy, cell proliferation and cell death mechanisms maintained by p53 protein. In mammalian cells, p53 is found in two diﬀerent form: Cytoplasmic and nuclear p53. Cytoplasmic p53 translocated to nucleus and regulate the transcription of genes involved in DNA repair, U-73122 arrest and apoptosis (Meek, 2015). Not only autophagy controlled cellular p53 level but also p53 regulated cellular autophagic activity at transcriptional level. Cytoplasmic form of p53 inhibited autophagy by mTORC1 activation and p53 depletion was able to induce autophagy in vivo (Tasdemir et al., 2008a). The ability of p53 to repress autophagy was linked to the localization of p53 on the ER (Tasdemir et al., 2008a, 2008b). In the nucleus, p53 activated AMPK, inhibited mTOR and subsequently initiated autophagy. Accu-mulating data suggested that p53 promotes autophagy through acti-vation of DAPK, DNA damage regulated autophagy modulator 1 (DRAM1), proapoptotic BCL-2 proteins (e.g., BAD, BAX, BNIP3, and PUMA), Sestrin1/2, and TSC2 (Tasdemir et al., 2008b). In response to genotoxic stress, p53 could transcriptionally activate ULK1 and ULK2, which in turn led to elevated autophagy level and contributed to cell death (Gao et al., 2011). Furthermore, in the absence of growth factors or in response to stress conditions, RB1 prevented cell cycle progression through inhibition of E2F transcription factor family members. RB-E2F pathway has been proposed to regulate autophagic response (Jiang et al., 2010) and E2F1 induced the expression of components of the autophagic machinery, including ATG1, ATG5 and LC3 (Polager et al., 2008).
A better understanding of the role of autophagy in regulation of cell proliferation, cell cycle arrest and cell death in tumor cells improve the potential for developing novel therapeutic strategies against malig-nancies.
3.1.3. Autophagy induces stress-related responses
Expression level of the cytoplasmic chaperone protein and signaling scaﬀold p62 is frequently found to be upregulated in human cancers (Liu and Ryan, 2012; Umemura et al., 2016). Accumulation of p62 correlated with increased endoplasmic reticulum (ER) stress and DNA damage in cancer cells (Duran et al., 2008; Moscat et al., 2007). Ad-ditionally, defects in the nuclear factor kappa B (NF- κB) and anti-oxidant nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) regulatory pathways were also found to be associated with
cellular p62 levels (Duran et al., 2008; Inami et al., 2011). Both in normal and cancer cells, p62 acts as an adaptor protein linking LC3-associated autophagic membranes with ubiquitin decorated misfolded proteins thereby mediating clearance of targets, including oncogenes.
In this context, suppression of autophagy lead to p62 accumulation, which in turn contributed to oncogenesis through increased levels of ER-stress and DNA-damage-stress (Moscat and Diaz-Meco, 2009). Ac-cordingly, accumulation of p62 was observed in the benign tumors developed in ATG5 or ATG7 depleted mouse models (Takamura et al., 2011). Moreover, loss of p62 in these mice was found to suppress tumor growth, suggesting a correlation between p62 accumulation and ade-noma formation (Liu and Ryan, 2012; Takamura et al., 2011).
3.1.4. Autophagy induces immune-response mechanisms
Autophagy contributes to innate immunity through facilitating several cellular responses including, cytokine production and phago-cytosis. Autophagy participated in adaptive immunity through its an-tigen presentation potential (Puleston et al., 2014; Puleston and Simon, 2014). Therefore autophagy has been suggested as a regulator of im-mune responses to combat with malignancies (Ma et al., 2013). Some dying malignant cells recruited antigen-presenting cells (APCs) and other cellular components of the immune system that may trigger both innate and/or adaptive antitumor immune responses (Gajewski et al., 2013). In this setting, defects in autophagy may suppress recognition and therefore prevent elimination of pre-malignant and malignant cells. Furthermore, autophagic response also limited tumor-induced in-flammation through clearance of inflammasomes (Nakahira et al., 2011) which may contain factors such as pro-inflammatory interleukins and damaged mitochondria (Galluzzi et al., 2015).
Viruses are considered to be responsible from the 10%–15% of human cancers worldwide. Mainly, viral infections are associated with increased genomic instability due to induction of changes at cellular, genetic and epigenetic levels resulting in tumor formation and pro-gression (Chen et al., 2014). A growing number of pathogenic infections promote carcinogenesis including, hepatitis B virus (hepatocellular carcinoma) (Poh et al., 2015), human herpesvirus 8 (linked to Kaposi's sarcoma) (Memar et al., 1995), human papillomavirus (cervical carci-noma) (Rijkaart et al., 2012), Epstein–Barr virus and Helicobacter py-lori (associated with gastric carcinoma) (Souza et al., 2018), Strepto-coccus bovis (colorectal carcinoma) (Ellmerich et al., 2000; Krishnan and Eslick, 2014), Salmonella enterica (gastrointestinal cancers) (Mughini-Gras et al., 2018), Chlamydia pneumoniae (lung cancer) (Chaturvedi et al., 2010), human T-cell lymphotropic virus (HTLV-1) (leukemia/lymphoma) (Kataoka et al., 2015) and SV40-Polyomavirus of the rhesus macaque (brain/osteosarcoma) (Mazzoni et al., 2015). Due to the involvement of a large population of pathogens in the tu-morigenesis, it is emerging to control the immune responses against invaders (Deretic et al., 2013). Clearance of these pathogens through selective autophagy mechanism termed as xenophagy. Xenophagy constitutes the first line of defense against infection and stimulates pathogen-specific adaptive immune response mechanisms (Gao et al., 2017; Mao and Klionsky, 2017; Zhao et al., 2018). Xenophagy-assisted removal of viruses could tightly be associated with innate immune and acquired immune responses. Viruses are capable of escaping from in-nate immunity by encoding diﬀerent genes associated with inhibition of apoptosis, autophagy and necroptosis. Even though targeting viruses for cancer treatment bears some limitations such as most of the findings obtained from in vitro, cell culture experiments; a selective type of autophagy xenophagy provides great potential for viral-infection asso-ciated cancers.