Triacetyl resveratrol upregulates miRNA‑200 and suppresses the Shh pathway in pancreatic cancer: A potential therapeutic agent

Fu,Junsheng; Shrivastava,Anju; Shrivastava,Sushant  K.; Srivastava,Rakesh  K.; Shankar,Sharmila

doi:10.3892/ijo.2019.4700

Triacetyl resveratrol upregulates miRNA‑200 and suppresses the Shh pathway in pancreatic cancer: A potential therapeutic agent

Authors:
- Junsheng Fu
- Anju Shrivastava
- Sushant K. Shrivastava
- Rakesh K. Srivastava
- Sharmila Shankar
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Affiliations: College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA, Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India, Kansas City VA Medical Center, Kansas City, MO 66128, USA
Published online on: January 28, 2019 https://doi.org/10.3892/ijo.2019.4700
Pages: 1306-1316

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Abstract

Trans‑3,4',5‑trihydroxystilbene (resveratrol) is a naturally occurring polyphenolic phytoalexin with marked anticancer activities, and is mainly found in grapes, berries and peanuts. However, due to a low bioavailability, it has not progressed to clinical practice for cancer treatment. Therefore, the aims of the present study were to examine the anticancer activities of the resveratrol derivative, triacetyl resveratrol (TCRV), in pancreatic cancer cells. Apoptosis was measured by fluorescence‑activated cell sorting and terminal deoxynucleotidyl transferase (TdT)‑mediated dUTP nick‑end labeling assays. Gene expression was measured by reverse transcription‑quantitative polymerase chain reaction. TCRV inhibited colony formation and induced apoptosis through caspase‑3 activation in human pancreatic cancer AsPC‑1 and PANC‑1 cells, whereas it exerted no effect on human pancreatic normal ductal epithelial cells (HPNE). TCRV inhibited epithelial‑mesenchymal transition (EMT) by upregulating the expression of E‑cadherin and suppressing the expression of N‑cadherin and the transcription factors, Snail, Slug and Zeb1. TCRV inhibited Zeb1 3'UTR‑luciferase activity through the upregulation of microRNA (miR)‑200 family members. The inhibitory effects of TCRV on pancreatic cancer cell migration and invasion were counteracted by anti‑miR‑200 family members. The inhibitory effects of TCRV on EMT and the induction of apoptosis were exerted through the suppression of the sonic hedgehog (Shh) pathway, and through the modulation of cyclin D1 and Bcl‑2 expression. The hyperactivation of the Shh pathway by either Shh protein or Gli1 overexpression abrogated the biological effects of TCRV. Taken together, the results of this study demonstrate that TCRV inhibits pancreatic cancer growth and EMT by targeting the Shh pathway and its downstream signaling mediators. TCRV inhibited EMT through the upregulation of miR‑200 family members. Since TCRV effectively inhibited the growth of human pancreatic cancer cells by modulating the Shh pathway, without affecting the growth of HPNE cells, our findings suggest the possible use of TCRV as a promising candidate for the treatment and/or prevention of pancreatic cancer.

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