Effect Of AMPK On Curcumin Induced Cell Death In CaOV3 Ovarian Cancer Cell

Ovarian cancer is the most deadly cancer of the female reproductive system.The five year survival rate is only 25 to 30 percent.Its high death rate is partly due to the lack of early detection and screening.Despite good initial response to chemotherapy,75%of women ultimately die of complications associated with disease progression.Furthermore,side effects and drug resistant are the main disadvantages of currently clinical applied chemotherapeutics.There is a thirsty demand for such drugs with low toxicity and high efficiency.Curcumin is one such agent.Curcumin,a yellow pigment derived from turmeric,is widely used as dietary spice in Asia.Curcumin possesses a number of pharmacological activities,such as anti-inflammation,anti-oxidant,anti-hyperlipemia and anti-cancer.Research over the last few decades has shown that curcumin suppresses transformation,proliferation and metastasis of tumors.These effects are mediated through its regulation of various transcription factors, growth factors,inflammatory cytokines,protein kinases and other enzymes.Yet,no published paper has considered AMPK as a molecular target of curcumin while berberine,an active component of coptidis rhizoma with similar characteristics and pharmacological actions,is capable of activating AMPK in adipocytes.Thus the question is raised that whether curcumin can activate AMPK?AMP activated protein kinase(AMPK)is an evolutionarily conserved Ser/Thr protein kinase,which serves as an energy sensor in all eukaryotic cell types.The AMPK system is a regulator of energy balance at both the cellular and whole-body levels.AMPK is activated by metabolic stress which is associated with an increased AMP/ATP ratio.Once activated, AMPK phosphorylates and inactivates a number of metabolic enzymes involved in ATP-consuming cellular events and also activates ATP-generating processes.AMPK not only function as a regulator of cellular energy but also serves as a regulator of cell proliferation and apoptosis.Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumor cells.The AMPK signaling network contains a number of tumor suppressor genes including LKB1,p53,TSC1 and TSC2.It is not surprising that AMPK is a promising therapeutic target for cancer.The present research is carried out to investigate the effect of curcumin on the AMPK signaling and whether AMPK is involved in curcumin induced cell death in ovarian cancer cell.Our study gives novel insights to the understanding of curcumin and provides pre-clinical data for its application.AIM:To investigate the effect of curcumin on AMPK signaling in CaOV3 cancer cell line and illustrate whether AMPK signaling is involved in curcumin induced cell death in CaOV3 cancer cell.METHODS:Protein phosphorylation was detected by Western Blotting.Cell viability was determined by MTT assay.RESULTS:Curcumin incubation strongly induced AMPK and p38 phosphorylation.Pretreatment of the cells with SB 203580(a p38 inhibitor)suppressed curcumin induced AMPK activation.Also, curcumin incubation increased the level of phospho-p53(Ser 15)and decreased the cell viability.Compound C(an AMPK inhibitor)or SB 203580 pretreatment attenuated p53 phosphorylation and alleviate cell death induced by curcumin.CONCLUTIONS:Curcumin induces AMPK activation in a p38 dependent manner.AMPK and p38 regulate p53 phosphorylation and mediate curcumin induced cell death in CaOV3 cancer cells.The major contributions of the present study lie in:Our original study reveals that AMPK is a neo molecular target of curcumin and this AMPK activation is associated with curcumin induced cell death in CaOV3 cancer cell.The present work gives novel insight to the understanding of curcumin and provides necessary experimental data for its clinical application.