Inducible COX-2-dependent apoptosis in human ovarian cancer cells

Abstract

Resveratrol is a naturally occurring trihydroxyl-diphenylethylene compound that has been shown experimentally to have beneficial effects in the treatment of cancer and cardiovascular disease. Resveratrol induces programmed cell death (apoptosis) in these cells and activates important signal transducing proteins including extracellular signal-regulated kinases (ERKs) 1 and 2 in cancer cells. Resveratrol also causes nuclear accumulation of the enzyme cyclooxygenase (COX)-2 and of the oncogene suppressor protein, p53. We have studied the molecular basis of the anticancer actions of resveratrol using human ovarian carcinoma (OVCAR-3) cells. Our findings include the following: (i) nuclear accumulation of COX-2 in resveratrol-treated cells is blocked by the ERK1/2 inhibitor, PD98059; (ii) an inhibitor of COX-2 activity, NS398, prevents accumulation of ERK1/2, COX-2, activated p53 and small ubiquitin-like modifier (SUMO-1) in the nucleus; (iii) apoptosis, quantitated by nucleosome enzyme-linked immunosorbent assay and the nuclear abundance of the pro-apoptotic protein, BcL-xs, were inhibited by NS398. This finding implicates nuclear COX-2 in p53-mediated apoptosis induced by resveratrol. Sumoylation is important to stabilization of p53 and a COX-2-SUMO-1 interaction suggests sumoylation of COX-2 in resveratrol-treated cells and (iv) chromatin immunoprecipitation studies showed binding of induced nuclear COX-2 to the promoter region of PIG3 and Bax, pro-apoptotic gene targets of transcriptionally active p53. Nuclear accumulation of activated ERK1/2 and sumolyated COX-2 are essential to resveratrol-induced pSer-15-p53-mediated apoptosis in human 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).…”

Newly-Recognized Small Molecule Receptors on Human Breast Cancer Cell Integrin αvβ3 that Affect Tumor Cell Behavior

“…It was also remarkable that the receptors for thyroid hormone and for resveratrol did not appear to interact functionally with one another. That is, both agents activated intracellular pools of MAPK (ERK1/2), but resveratrol was pro-apoptotic (Lin H et al, 2008a;Lin C et al, 2011) whereas thyroid hormones (T 4 , T 3 ) were anti-apoptotic (Lin H et al, 2008b), as noted above. Such observations suggested that the results of any efficacy testing of resveratrol as a chemotherapeutic agent in the presence of physiologic concentrations of thyroid hormone in vitro or in the intact animal with a normal pituitary-thyroid axis may be difficult to interpret (see below).…”

“…An Arg-Gly-Asp (RGD) peptide prevents both the pro-apoptotic activity of resveratrol and the anti-apoptotic activity of thyroid hormone, indicating that the receptor is near the RGD recognition site on the integrin that was mentioned above (see section on Thyroid Hormone Action). The interactions of tetrac with either T 4 or resveratrol, however, indicate that the two integrin binding sites are distinct, in that while tetrac inhibits the proliferative action of T 4 in cancer cells, tetrac does not inhibit the pro-apoptotic actions of resveratrol (Lin C et al, 2011). Our own studies of the mechanism by which resveratrol may act to induce apoptosis in tumor cells have revealed several unexpected findings.…”

“…These activities include extension of lifespan in C. elegans (Zarse et al, 2010) and remarkable anti-cancer properties (Pezzuto et al, 2011;Hsieh et al, 2011;Lin, C et al, 2011). Substantial attention has been devoted to the metabolism of this agent because of its rapid disappearance from the circulation post-administration to intact animals and its cellular uptake and chemical modification (Delmas et al, 2011).…”

Chemically-Induced DNA Damage, Mutagenesis, and Cancer

“…Resveratrol activates ERK1/2 at low concentrations (1 pM-10 μM), but at higher concentrations (50-100 μM) can inhibit MAPK in human neuroblastoma SH-SY5Y cells [142]. In contrast, resveratrol activates ERK1/2 in prostate [143], breast [144,145], glial [146], head and neck [147], and ovarian cancer cells [148]. MAPKs in a constitutively active state are necessary to maintain the malignant state; however, short-term activation of MAPK may drive the cells to apoptosis [149].…”