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Resveratrol induces AMPK-dependent MDR1 inhibition in colorectal cancer HCT116/L-OHP cells by preventing activation of NF-κB signaling and suppressing cAMP-responsive element transcriptional activity

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Tumor Biology

Abstract

Resveratrol, a natural polyphenolic compound found in foods and beverages, has attracted increasing attention in recent years because of its potent chemopreventive and anti-tumor effects. In this study, the effects of resveratrol on the expression of P-glycoprotein/multi-drug resistance protein 1 (P-gp/MDR1), and the underlying molecular mechanisms, were investigated in oxaliplatin (L-OHP)-resistant colorectal cancer cells (HCT116/L-OHP). Resveratrol downregulated MDR1 protein and mRNA expression levels and reduced MDR1 promoter activity. It also enhanced the intracellular accumulation of rhodamine 123, suggesting that resveratrol can reverse multi-drug resistance by downregulating MDR1 expression and reducing drug efflux. Resveratrol treatment also reduced nuclear factor-κB (NF-κB) activity, reduced phosphorylation levels of IκBα, and reduced nuclear translocation of the NF-κB subunit p65. Moreover, downregulation of MDR1 expression and promoter activity was mediated by resveratrol-induced AMP-activated protein kinase (AMPK) phosphorylation. The inhibitory effects of resveratrol on MDR1 expression and cAMP-responsive element-binding protein (CREB) phosphorylation were reversed by AMPKα siRNA transfection. We found that the transcriptional activity of cAMP-responsive element (CRE) was inhibited by resveratrol. These results demonstrated that the inhibitory effects of resveratrol on MDR1 expression in HCT116/L-OHP cells were closely associated with the inhibition of NF-κB signaling and CREB activation in an AMPK-dependent manner.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81473482), the Putuo District Committee of Science and Technology, Shanghai, China (No. 201102), and Xinglin Scholars of Shanghai University of Traditional Chinese Medicine. This research was also supported by the construct program of the key discipline of State Administration of Traditional Chinese Medicine of the People’s Republic of China.

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    Authors and Affiliations

    1. Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai, 200062, China

      Ziyuan Wang, Long Zhang, Zhenhua Ni, Jian Sun, Hong Gao, Zhuoan Cheng, Jianhua Xu & Peihao Yin

    2. Department of Clinical Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai, 200062, China

      Jianhua Xu

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    1. Ziyuan Wang
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    Correspondence to Jianhua Xu or Peihao Yin.

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    Ziyuan Wang and Long Zhang contributed equally to this work.

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    Wang, Z., Zhang, L., Ni, Z. et al. Resveratrol induces AMPK-dependent MDR1 inhibition in colorectal cancer HCT116/L-OHP cells by preventing activation of NF-κB signaling and suppressing cAMP-responsive element transcriptional activity. Tumor Biol. 36, 9499–9510 (2015). https://doi.org/10.1007/s13277-015-3636-3

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