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.
Int J Oncol. 2019 Apr;54(4):1306-1316. doi: 10.3892/ijo.2019.4700. Epub 2019 Jan 28.
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.
反式-3,4',5-三羟基二苯乙烯（白藜芦醇）是一种具有显著抗癌活性的天然多酚类植物抗毒素，主要存在于葡萄、浆果和花生中。然而，由于生物利用度低，它尚未在癌症治疗的临床实践中得到应用。因此，本研究旨在研究白藜芦醇衍生物三乙酰白藜芦醇（TCRV）在胰腺癌细胞中的抗癌活性。通过荧光激活细胞分选和末端脱氧核苷酸转移酶（TdT）介导的 dUTP 缺口末端标记测定法测量细胞凋亡。通过逆转录定量聚合酶链反应测量基因表达。TCRV 通过激活 caspase-3 抑制人胰腺癌细胞 AsPC-1 和 PANC-1 的集落形成并诱导细胞凋亡，而对人胰腺正常导管上皮细胞（HPNE）则没有作用。TCRV 通过上调 E-钙黏蛋白的表达和抑制 N-钙黏蛋白和转录因子 Snail、Slug 和 Zeb1 的表达来抑制上皮-间充质转化（EMT）。TCRV 通过上调 microRNA（miR）-200 家族成员来抑制 Zeb1 3'UTR-荧光素酶活性。抗 miR-200 家族成员可逆转 TCRV 对胰腺癌细胞迁移和侵袭的抑制作用。TCRV 通过抑制 sonic hedgehog（Shh）途径及其对 cyclin D1 和 Bcl-2 表达的调节来发挥对 EMT 和细胞凋亡的诱导作用。Shh 蛋白或 Gli1 过表达引起的 Shh 途径超活化消除了 TCRV 的生物学效应。总之，本研究结果表明，TCRV 通过靶向 Shh 途径及其下游信号转导介质来抑制胰腺癌细胞的生长和 EMT。TCRV 通过上调 miR-200 家族成员来抑制 EMT。由于 TCRV 通过调节 Shh 途径有效抑制人胰腺癌细胞的生长，而不影响 HPNE 细胞的生长，我们的研究结果表明，TCRV 可能作为治疗和/或预防胰腺癌的有前途的候选药物。
