Midostaurin br Another autophagy regulatory components PI K
Another autophagy regulatory components PI3K-AKT-mTORC1 and the IKK pathways are also involved in the regulation of autophagy during ECM detachment (Chen and Debnath, 2013). In line with these findings, autophagy inhibition attenuated pulmonary metastasis of HCC Midostaurin in nude mice, which seemed to correlate with enhanced anoikis (Macintosh et al., 2012). Furthermore, in this context autophagy played a critical role in invasiveness and migration of cancer cells. Depletion of ATG12 decreased the invasive capacity of glioma cells (Macintosh et al., 2012). Similarly, autophagy inhibition or p62 knockdown reduced the rate of invasion and migration in vitro and resulted in metabolic defects in glioblastoma stem cells (Galavotti et al., 2013). Additionally, de-fective autophagy correlated with reduced secretion of proinvasive cytokines such as the interleukin-6 (IL6) (Kenific and Debnath, 2015). In agreement with these observations, addition of IL6 into Ras-trans-formed epithelial cells was able to partly restore the invasive capacity of the cancer cells, which was reduced due to autophagy inhibition European Journal of Pharmaceutical Sciences 134 (2019) 116–137
(Lock et al., 2014). Evidence also suggested that autophagy was acti-vated through toll-like receptors (TLRs) which mediated secretion of proinvasive factors, including IL6 (Zhan et al., 2014). Furthermore, autophagy-dependent secretion was also important for the invasiveness of HCC cells as IL6 stimulated TGFβ signaling and promoted EMT (O'Reilly et al., 2014).
3.2.4. Autophagy regulates unfolded protein response (UPR) in cancer cells Abnormalities in calcium homeostasis, oxidative stress and condi-tions leading to protein glycosylation or folding defects etc. resulting in the accumulation of misfolded and/or unfolded proteins in the ER lumen, a condition known as ER stress (Senft and Ronai, 2015). ER stress driven by the accumulation of unfolded proteins potentiated signaling from ER to nucleus termed as the unfolded protein response (UPR). Once activated, UPR enhances the expression of proteins that mediate proper protein folding in the ER such as the chaperones. In-ability to restore the function of ER leads to the removal of the aﬀected cells by apoptosis (Senft and Ronai, 2015). Autophagy functions as a critical mechanism to cope with ER stress promoting survival of the cancer cells (Nagelkerke et al., 2014). The PERK-arm of the UPR is important for the activation of autophagy in majority of the cancer cells. Both the eIF2α phospho-mutant constructs and dominant-nega-tive PERK was shown to prevent the conversion of LC3-I to LC3-II (Kouroku et al., 2007). Radiotherapy-based treatment was found to induce PERK-dependent autophagy in breast cancer cells, which were sensitized to radiotherapy by both pharmacological inhibition of au-tophagy and silencing of the PERK-signaling (Chaachouay et al., 2011). Additionally, tamoxifen treatment of breast cancer cells induced autophagy, which partly regulated by ATF4-induced LAMP3 and/or by GRP78-dependent inhibition of mTOR (Nagelkerke et al., 2014). Simi-larly, bortezomib treatment of breast cancer cells led to increase in LC3B and autophagy in an ATF4-dependent manner, protecting against cell death and inducing bortezomib-resistance (Milani et al., 2009). Furthermore, autophagy can also be activated through the IRE1-arm of UPR-signaling pathway in some cancer types. For example, ER stress induced by tunicamycin, thapsigargin or amino acid starvation was able to induce autophagy in neuroblastoma cells through activation of the IRE1-arm of ER-stress mechanisms (Ogata et al., 2006). Finally, ER stress also induced autophagy through upregulating cellular levels of GRP78. GRP78 expression correlated with increased upregulation of LC3 and Beclin-1, enhanced autophagic flux and increased number of
autophagosomes in neural cells.
Human papilloma virus is a major leading source of cervix cancer and in collaboration with NF-kB pathway contributed to proliferation, invasion and metastasis. In human cervical cancer cells, ER-stress in-ducers potentiated autophagic activity through NF-κB pathway and resulted in cell death (X. Zhu et al., 2017). An inhibitor of NF-κB, quinazolinediamine (QZN) reduced Brefeldin A-induced cell death and autophagy.
As another example, in human colorectal cancer, a novel tyrosine kinase inhibitor Apatinib induced both autophagy and apoptosis through IRE-1α arm of ER-stress (Cheng et al., 2018). Apatinib favored for the protective role of autophagy providing an acquired resistance to apatinib treatment in colorectal cancer cells. Therefore targeting au-tophagic activity is a promising treatment strategy as a combinatory treatment of apatinib and CQ (Cheng et al., 2018). r>