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.
Highlights
The phosphoinositide 3-kinase (PI3K)/Akt and mammalian target of rapamycin signaling pathway is important for many cellular functions such as cell proliferation, growth control, metabolism, and cell survival
We investigated whether natural compounds enhance NVP-BEZ235-induced PI3K-Akt-mammalian target of rapamycin (mTOR) signaling inhibition and cell death in human renal carcinoma Caki cells, and the molecular mechanisms underlying co-treatment with curcumin and NVP-BEZ235 were analyzed in human renal carcinoma Caki cells
NVP-BEZ235 inhibits the activation of PI3K/Akt and mTOR signaling, which is important for cell survival, and induces cell death in non-small lung cancer [49] and breast cancer cells [50]
Summary
The phosphoinositide 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathway is important for many cellular functions such as cell proliferation, growth control, metabolism, and cell survival. PI3K-Akt-mTOR is activated via multiple mechanisms, including phosphatase and tensin homolog (PTEN) mutation (PI3K-Akt signaling negative regulator) [1,2], Akt overexpression [3,4], and the activation of upstream signaling pathways (receptor tyrosine kinase and Ras) [5,6] that are associated with cancer cell proliferation, tumor growth, metastasis, and cell survival [7,8,9,10]. TORC1 is composed of mTOR, mammalian LST8 (mLST8), proline-rich Akt substrate 40 (PRAS40), and raptor (regulatory-associated protein of mTOR), while TORC2 contains mTOR, mLST8 (GbL), mSIN1, PRR5 (protor), and rictor (rapamycin-insensitive companion of TOR) [11,12,13,14]. Only TORC1 inhibition can activate TORC2 signaling, resulting in the activation of Akt [18]
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