Curcumin Significantly Enhances Dual PI3K/Akt and mTOR Inhibitor NVP-BEZ235-Induced Apoptosis in Human Renal Carcinoma Caki Cells through Down-Regulation of p53-Dependent Bcl-2 Expression and Inhibition of Mcl-1 Protein Stability

Abstract

The PI3K/Akt and mTOR signaling pathways are important for cell survival and growth, and they are highly activated in cancer cells compared with normal cells. Therefore, these signaling pathways are targets for inducing cancer cell death. The dual PI3K/Akt and mTOR inhibitor NVP-BEZ235 completely inhibited both signaling pathways. However, NVP-BEZ235 had no effect on cell death in human renal carcinoma Caki cells. We tested whether combined treatment with natural compounds and NVP-BEZ235 could induce cell death. Among several chemopreventive agents, curcumin, a natural biologically active compound that is extracted from the rhizomes of Curcuma species, markedly induced apoptosis in NVP-BEZ235-treated cells. Co-treatment with curcumin and NVP-BEZ235 led to the down-regulation of Mcl-1 protein expression but not mRNA expression. Ectopic expression of Mcl-1 completely inhibited curcumin plus NVP-NEZ235-induced apoptosis. Furthermore, the down-regulation of Bcl-2 was involved in curcumin plus NVP-BEZ235-induced apoptosis. Curcumin or NVP-BEZ235 alone did not change Bcl-2 mRNA or protein expression, but co-treatment reduced Bcl-2 mRNA and protein expression. Combined treatment with NVP-BEZ235 and curcumin reduced Bcl-2 expression in wild-type p53 HCT116 human colon carcinoma cells but not p53-null HCT116 cells. Moreover, Bcl-2 expression was completely reversed by treatment with pifithrin-α, a p53-specific inhibitor. Ectopic expression of Bcl-2 also inhibited apoptosis in NVP-BE235 plus curcumin-treated cells. In contrast, NVP-BEZ235 combined with curcumin did not have a synergistic effect on normal human skin fibroblasts and normal human mesangial cells. Taken together, combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level.

Curcumin inhibits cell proliferation and promotes apoptosis of laryngeal cancer cells through Bcl-2 and PI3K/Akt, and by upregulating miR-15a

“…Suppression of miR-15a expression was able to reverse the effects of curcumin in AMC-HN-8 cells. Seo et al (24) reported that curcumin significantly promoted NVP-BEZ235 (a PI3K/Akt and mammalian target of rapamycin inhibitor)-induced apoptosis through Bcl-2 expression in human renal carcinoma Caki cells. Zhao et al (25) indicated that curcumin induces apoptosis via inhibition of the PI3K/Akt signaling pathway in pancreatic cancer cells.…”

The mTOR Signalling Pathway in Cancer and the Potential mTOR Inhibitory Activities of Natural Phytochemicals

“…On the other hand, activation of Akt pathway by recombinant full-length human active Akt1 protein (rAkt1) inhibited curcumin-induced autophagy and decreased curcumin-inhibited phosphorylation of Akt and p70S6K, suggesting that curcumin-induced inactivation of Akt/mTOR/p70S6K pathway plays a role in induction of autophagy (Aoki et al, 2007). As combined treatment, curcumin and dual PI3K/Akt and mTOR inhibitor induce apoptosis through p53-dependent Bcl-2 mRNA downregulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level in human renal carcinoma Caki cells (Seo et al, 2014).…”

Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells

“…The present in vitro study revealed that NVP-BEZ235 not only downregulated mTOR activity, as indicated by the dephosphorylation of Ser2448 p-mTOR, but also decreased Akt activity, as indicated by the decreased phosphorylation of Ser473 p-Akt. Depending on the tumor cell type, inhibitors of PI3K/Akt/mTOR signaling have been revealed to function as inhibitors of cell proliferation, by leading to cell cycle arrest, and also as cytotoxic agents, by inducing apoptosis (20)(21)(22). Using the human MCC MKL-1 cell line, it was revealed that NVP-BEZ235 demonstrated cytostatic action and led to the accumulation of the cells almost exclusively in the G1 phase.…”