Inhibition of ATF4-mediated elevation of both autophagy and AKT/mTOR was involved in antitumorigenic activity of curcumin.

Curcumin, a natural hydrophobic polyphenol, carries significant anticancer activity. The protein kinase B (AKT)/the mammalian target of the rapamycin (mTOR) pathway and autophagy are well known to be involved in carcinogenesis, and usually, inhibition of mTOR is the main reason to promote autophagy. In this study, however, autophagy and mTOR were found to be inhibited simultaneously by curcumin treatments, and both of them played an important role in the effect of curcumin on suppressing the growth of A549 cells. Tunicamycin (TM), the activator of Endoplasmic Reticulum (ER) stress, increased both autophagy and AKT/mTOR, while curcumin could significantly decrease TM-induced autophagy and AKT/mTOR. Furthermore, curcumin could inhibit TM-induced aerobic glycolysis in A549 cells, and decrease the level of cycle-related and migration-related proteins. Blocking activating transcription factor 4 (ATF4) by siRNA strongly reduced both the expression of autophagy-related proteins and AKT/mTOR. ChIP assay illustrated that ATF4 protein could bind to the promotor sequence of either ATG4B or AKT1. The transplantation tumor experiment showed that the weight and volume of the transplanted tumors were reduced significantly in the BALB/c mice subcutaneously injected with A549 cells treated with curcumin. Moreover, intranasal administration of curcumin decreased the protein level of autophagy, AKT/mTOR and ER stress in lung tissues of BALB/c mice. Taken together, our results demonstrated that inhibition of ER stress-dependent ATF4-mediated autophagy and AKT/mTOR pathway plays an important role in anticancer effect of curcumin.