Fig. 4

Diagram illustrates the dominating signaling pathways involving Sal- induced autophagy. Sal is able to induce intensive autophagic flux than commonly used autophagic inducers such as chloroquine, as many autophagy-initiated pathways being activated by Sal. ROS is deemed to play a key role in it. Pretreating with NAC, an ROS inhibitor, suppresses the autophagic flux being confirmed by different researchers. Sal activates AMPK signaling pathway, MAPK signaling pathway and ER stress initiating autophagy, and inhibits PI3K/AKT/mTORC1 axis simultaneously. (1) AMPK activates autophagy by directly binding and activating ULK1 complex through phosphorylation of Ser 317 [110, 111]. Enhanced stimulatory TSC2 phosphorylation at Ser-1387 by AMPK, and reduced inhibitory TSC2 phosphorylation at Ser-939/Thr-1462 catalyzed by AKT augmented TSC2/TSC1 activity, which led to mTORC1 inhibition. AMPK-mediated raptor phosphorylation further reduced mTOR’s kinase function and mTORC1 activity [42]; (2) Moreover, it has been reported that ROS suppress PI3K/AKT/mTOR signaling [112]. In addition, it’s demonstrated that Sal suppresses AKT1 activity through ATF4-DDIT3/CHOP-TRIB3-AKT1 axis in human cancer cells after activation of ER stress response, resulting in MTOR inhibition and autophagy consequently [43]; (3) ROS inactivates MAPK phosphatases [113]. This subsequently leads to the phosphorylation of JNK, and of its target the transcription factor JUN. JNK activation may promote autophagy through induction of ATG7 [94], or by phosphorylation of BCL2, which leads to dissociation of BCL2 from Beclin-1 [95]