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
Authors: Taeg Kyu Kwon
Il Je Cho
Bo Ram Seo
Sang Chan Kim
Kyoung-Jin Min
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: PI3K/Akt; mTOR; signaling pathways; cancer cells; NVP-BEZ235
Affiliations: Department of Immunology, School of Medicine, Keimyung University, Daegu, South Korea., College of Oriental Medicine, Daegu Haany University, Gyeongsan, Korea; Medical Research Center for Globalization of Herbal Formulation, Daegu Haany University, Gyeongsan, Korea.

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. 

Retracted: No

PubPeer comments:
 March 2016 correction found here: https: journals.plos.org plosone article?id=10.1371 journal.pone.0151886 It reads: *The authors would like to correct Fig 2, as errors were introduced in the preparation of the figure for publication. In the lower panel of Fig 2B, the Curcumin 30 u03bcM + panel and the NVP-BEZ235 2u03bcM + panel are erroneously derived from the same image. A corrected version of Fig 2 is available here. The authors confirm that these changes to not alter their findings and have provided the underlying images as Supporting Information.* Here is the original Figure 2 as reported to the journal in 2014, with the duplication marked with red boxes. I thank the authors and journal for correcting this error. ![file] ,