Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling.

Abstract

New cytotoxic agents are urgently needed for the treatment of advanced ovarian cancer because of the poor long-term response of this disease to conventional chemotherapy. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity; however, the mechanism of curcumin-induced cytotoxicity in ovarian cancer cells remains a mystery. In this study we show that curcumin exhibited time- and dose-dependent cytotoxicity against monolayer cultures of ovarian carcinoma cell lines with differing p53 status (wild-type p53: HEY, OVCA429; mutant p53: OCC1; null p53: SKOV3). In addition, p53 knockdown or p53 inhibition did not diminish curcumin killing of HEY cells, confirming p53-independent cytotoxicity. Curcumin also killed OVCA429, and SKOV3 cells grown as multicellular spheroids. Nuclear condensation and fragmentation, as well as DNA fragmentation and poly (ADP-ribose) polymerase-1 cleavage in curcumin-treated HEY cells, indicated cell death by apoptosis. Procaspase-3, procaspase-8, and procaspase-9 cleavage, in addition to cytochrome c release and Bid cleavage into truncated Bid, revealed that curcumin activated both the extrinsic and intrinsic pathways of apoptosis. Bax expression was unchanged but Bcl-2, survivin, phosphorylated Akt (on serine 473), and total Akt were downregulated in curcumin-treated HEY cells. Curcumin also activated p38 mitogen-activated protein kinase (MAPK) without altering extracellular signal-regulated kinase 1/2 activity. We conclude that p53-independent curcumin-induced apoptosis in ovarian carcinoma cells involves p38 MAPK activation, ablation of prosurvival Akt signaling, and reduced expression of the antiapoptotic proteins Bcl-2 and survivin. These data provide a mechanistic rationale for the potential use of curcumin in the treatment of ovarian cancer.

• Authors: Jane L Watson, Anna Greenshields, Richard Hill, Ashley Hilchie, Patrick W Lee, Carman A Giacomantonio, David W Hoskin
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 49 Issue 1 Pg. 13-24 (Jan 2010) ISSN: 1098-2744 [Electronic] United States
• PMID: 19676105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Proto-Oncogene Proteins c-bcl-2
• Survivin
• Tumor Suppressor Protein p53
• Oncogene Protein v-akt
• p38 Mitogen-Activated Protein Kinases
• Curcumin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects)
• Curcumin (pharmacology)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Enzyme Activation (drug effects)
• Female
• Humans
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins (metabolism)
• Oncogene Protein v-akt (metabolism)
• Ovarian Neoplasms (genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA Interference
• Signal Transduction (drug effects)
• Spheroids, Cellular (drug effects, metabolism)
• Survivin
• Time Factors
• Tumor Suppressor Protein p53 (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)