Roles of Autophagy Induced by Natural Compounds in Prostate Cancer

Figure 2

Schematic representation of the molecular regulation of autophagy. Growth factor signalling activates the PI3K/Akt/mTORC1 pathway resulting in autophagy inhibition. mTORC1 is also activated by amino acids and nutrient rich conditions, whereas starvation and oxidative stress induce autophagy via mTORC1 inhibition. Starvation and hypoxia can also induce autophagy through AMPK activation. Beclin 1-Vps34-Vps15 complex (or PI3KCIII complex) is required for the induction of autophagy, and the interaction between its components is regulated by interacting proteins (blue boxes): Rubicon, Mcl-1, and Bcl-XL/Bcl-2 are negative regulators, whereas proteins, such as UVRAG, Atg14, Bif-1, VMP-1, and Ambra-1, through their interaction with Beclin-1 and Vps34, promote the activity of the PI3KCIII complex inducing autophagy. Numerous kinases (red boxes) are involved in autophagy regulation: ERK and JNK-1 can induce autophagy by releasing Bcl-2 inhibition through its phosphorylation; Akt inhibits autophagy via Beclin 1 phosphorylation, whereas DAPK-mediated phosphorylation of Beclin 1 promotes autophagy. Finally, PKA and PKC negatively regulate autophagy acting on LC3. Atg4, Atg3, Atg7 and Atg10 are autophagy-related proteins which mediate the formation of the LC3-II complex and the Atg12-Atg5-Atg16L complex, and they may represent additional control points in the autophagic pathway.