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Resveratrol Induces Apoptosis in Thyroid Cancer Cell Lines via a MAPK- and p53-Dependent Mechanism

Medical Research Service, Stratton Veterans Affairs Medical Center (A.S., F.B.D., H.-Y.L., P.J.D.), the Clinical Research Institute, Albany Medical College (F.B.D., P.J.D.), and the Wadsworth Center, New York State Department of Health (P.J.D.), Albany, New York 12208

Address all correspondence to: Hung-Yun Lin, Ph.D., Clinical Research Institute MC-16, Albany Medical College, Albany, New York 12208. E-mail: . Address all requests for reprints to: Dr. Paul J. Davis, Clinical Research Institute, MC-16, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208. linhungyun{at}hotmail.com

Abstract

Two papillary thyroid carcinoma (PTC) and two follicular thyroid carcinoma (FTC) cell lines treated with resveratrol (RV), 1–10 µM, showed activation and nuclear translocation of MAPK (extracellular signal-regulated kinase 1/2). Cellular abundance of the oncogene suppressor protein p53, serine phosphorylation of p53, and abundance of c-fos, c-jun, and p21 mRNAs were also increased by RV. Inhibition of the MAPK pathway by either H-ras antisense transfection or PD 98059, an MAPK kinase inhibitor, blocked these RV-induced effects. Addition of pifithrin-, a specific inhibitor of p53, or transfection of p53 antisense oligonucleotides caused decreased RV-induced p53 and p21 expression in PTC and FTC cells. Studies of nucleosome levels estimated by ELISA and of DNA fragmentation showed that RV induced apoptosis in both papillary and follicular thyroid cancer cell lines; these effects were inhibited by pifithrin- and by p53 antisense oligonucleotide transfection. PD 98059 and H-ras antisense transfection also blocked induction of apoptosis by RV. Thus, RV acts via a Ras-MAPK kinase-MAPK signal transduction pathway to increase p53 expression, serine phosphorylation of p53, and p53-dependent apoptosis in PTC and FTC cell lines.

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