Resveratrol Suppresses Growth of Human Ovarian Cancer Cells in Culture and in a Murine Xenograft Model: Eukaryotic Elongation Factor 1A2 as a Potential Target

Abstract

The eukaryotic elongation factor 1A2 (eEF1A2) is known to retain oncogenic potential and is recognized as a novel target for cancer prevention and therapy. Resveratrol (trans-3,4 ¶,5-trihydroxystilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the growth-inhibitory effects of resveratrol in human ovarian cancer PA-1 cells, considering eEF1A2 as a potential molecular target. Pretreatment with resveratrol attenuated proliferation of serum-starved PA-1 cells stimulated with insulin or serum. Resveratrol also activated caspase-9, -7, and -3 and induced apoptosis in PA-1 cells in the presence of insulin or serum. Insulin or serum stimulation of PA-1 cells resulted in the marked induction of eEF1A2, which was suppressed by pretreatment with resveratrol. Moreover, resveratrol inhibited insulin-or serum-induced soft-agar colony formation in eEF1A2-transfected NIH3T3 cells. An antibody array directed to assess the phosphorylation of protein kinases revealed that treatment with insulin or serum induced the phosphorylation of Akt in PA-1 cells. Pharmacologic inhibition of Akt with LY294002 abrogated insulin-or serum-induced eEF1A2 expression and increased the caspase-3 activity. In another experiment, i.p. administration of resveratrol retarded the growth of PA-1 cell xenograft and the expression of eEF1A2 in athymic nude mice in association with decreased bromodeoxyuridine positivity, reduced expression of proliferating cell nuclear antigen, increased the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and caspase-3 staining, and diminished CD31 positivity. Taken together, eEF1A2 may be considered as a potential molecular target for the antiproliferative effects of resveratrol in PA-1 ovarian cancer cells.

Resveratrol Exerts Differential Effects in Vitro and in Vivo against Ovarian Cancer Cells

“…Several studies have previously demonstrated marked antitumor activities of resveratrol against various ovarian cancer cells. Resveratrol has been shown to inhibit both the growth and proliferation of human ovarian cancer cells, such as OVCAR-3, PA-1 and SKOV-3, through induction of apoptosis, DNA damage and S-phase arrest (Yang et al, 2003;Tyagi et al, 2005;Raj et al, 2008;Lee et al, 2009;Björklund et al, 2011;Lin et al, 2011;Marimuthu et al, 2011). Resveratrol induced cell death and growth inhibition in A1947, A2780, CaOV3, ES-2, SKOV3 and TOV112D cells by autophagocytosis and inhibition of glycolysis (Opipari et al, 2004;Kueck et al, 2007).…”

“…There are only two other in vivo studies in which antiovarian cancer activities of resveratrol have been tested. According the study conducted by Lee and colleagues (Lee et al, 2009), intraperitoneal (i.p.) administration of resveratrol (50 or 100 mg/kg, once daily for 4 weeks) in female Balb/c (nu/nu) mice xenografted with PA-1 cells, starting the treatment 10 days following tumor cell implantation, retarded the growth of tumor with simultaneous decrease in cell proliferation and apoptosis.…”

Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer

“…Resveratrol inhibits proliferation and induces apoptosis in various cancer cell lines, including breast, prostate, colon, and ovarian cancer cells [2]. In nude mice implanted with human ovarian cancer cells, resveratrol suppressed tumor growth when it was administered intraperitoneally, and apoptotic features were observed in the tumor tissues [22,34]. Resveratrol also enhanced the efficacy of cisplatin and doxorubicin in ovarian cancer cells, while reducing the doxorubicin-related cardiac toxicity [51].…”

Induced growth of BG-1 ovarian cancer cells by 17β-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression

“…Ovarian cancer is the leading cause of death from gynecologic malignancies (3,20). The median survival rate of ovarian cancer patients in advanced stage is 5 years and remains low, although anticancer therapies are currently being examined (21).…”