6 Class (target) Beclin 1 DNA damage ER stressors Farnesyltransferase inhibitors Golgi-associated agents HDAC inhibitors Mitochondrial agents mTOR inhibitors Pathogens Proteasome inhibitors International Journal of Cell Biology Compounds ABT-737 Fenretinide Xestospongin B Okadaic acid UV ROS Camptothecin A23187 Thapsigargin Tunicamycin Brefeldin A Bortezomib Sorafenib Manumycin A FTI-276 Lonafarnib Brefeldin A Paclitaxel SAHA Valproic acid FK228 Selenite Resveratrol Rapamycin Berberine Torin1 Ku-0063794 PM02734 Bacteria HSV-1 MG-132 Glidobactin A Table 1: Proautophagics. Autophagic mechanisms Disruption of Bcl-2/Bcl-xL binding to Beclin 1 Increase in Beclin 1 expression Disruption of the complex formed by IP3R and Beclin 1 Increase in Beclin 1 pathways p53 activation PTEN upregulation mTOR suppression GRP78 induction Increase of Ca2+ in cytosol PERK/elF2α pathway Induction of GRP78 and GRP94 Unfolded protein response Inhibition of mTOR signaling Akt downregulation and mTOR phosphorylation Interruption of traﬃcking of N-linked glycoproteins Fragmentation of Golgi apparatus Downregulation of Akt and mTOR activity Increase in mitochondrial ROS Nuclear translocation of AIF Degradation of mitochondrial proteins Inhibition of mitochondrial function mTORC1 inhibition Akt suppression and p38 MAPK upregulation Inhibition of mTORC1 and mTORC2 Dephosphorylation of mTORC1 substrate 4E-BP1 DAPK activation Ubiquitin-p62-NDP52 pathway PKR and eIF2α activation ER stress induced by misfolded proteins Catalytic subunits of 20S proteasome Reference [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [7] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] DNA damage induces autophagy, but its role in the DNA damage response is still unclear. Recent reports using the DNA-damaging agents, camptothecin, etoposide (VP-16), tomozolomide, and p-anilioaniline (p-aminodiphenylamine), demonstrate that cells, in addition to initiating cell cycle arrest, also initiate autophagy. p53 is a central regulator of apoptosis induced by DNA damage. Interestingly, p53 is a bidirectional regulator of autophagy. p53 activation also leads to upregulation of the PTEN, an inhibitor of the PI3K/Akt signaling pathway, and TSC2, at the transcriptional level, which may contribute to the long-term suppression of mTOR [56]. 9.1.3. ER Stressors. Autophagy was induced by chemicals, such as A23187, tunicamycin, thapsigargin, and brefeldin A that cause ER stress [57]. The calcium ionophore A23187 induced the expression of BiP/GRP78 protein, which is an ER stress marker protein. GRP78, through maintenance of ER structure and homeostasis, facilitates autophagy. Dis- turbances in normal ER processes lead to an evolutionarily conserved cell stress response, referred to as the unfolded protein response (UPR). Tunicamycin, an inhibitor of N- glycosylation, is a potent stimulator of ER stress. The link between tunicamycin-induced ER stress and autophagy was the PERK/elF2α pathway. Thapsigargin, an inhibitor of the ER calcium transporters, generates Ca2+-store depletion within the ER and simultaneously increases the Ca2+ level in the cytosol. Brefeldin A (an inhibitor of vesicle transport between the ER and Golgi) can increase the expression of both glucose-regulated proteins GRP78 and 94, which disrupt some functions of the ER. The inhibition of the 26S proteasome by the dipeptide boronic acid bortezomib (velcade) leads to the accumulation of misfolded proteins, resulting in ER stress followed by a coordinated cellular UPR response [58]. Induction of autophagy by bortezomib is dependent on the proteasomal stabilisation of ATF4 and upregulation of LC3B by ATF4. Sorafenib (nexavar), a potent multikinase inhibitor, inhibited phosphorylation of Stat3 and expression of cyclins, D and E, and exerted signiﬁcant antitumor activity through inhibition of mTOR signaling. In addition, sorafenib induced autophagy in human hepatocel- lular carcinoma cells through mechanisms that involved ER