Journal Article

Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells

Batra, S, Srivastava, S K, Sahu, R P

2009

Overview

Curcumin has been shown to inhibit the growth of various types of cancer cells; however, at concentrations much above the clinically achievable levels in humans. The concentration of curcumin achieved in the plasma after oral administration in humans was estimated to be around 1.8  μ M . Here, we report that treatment of BxPC-3 human pancreatic cancer cells with a low and single exposure of 2.5  μ M curcumin for 24 h causes significant arrest of cells in the G2/M phase and induces significant apoptosis. Immunoblot studies revealed increased phosphorylation of H2A.X at Ser-139 and Chk1 at Ser-280 and a decrease in DNA polymerase- β level in curcumin-treated cells. Phosphorylation of H2A.X and Chk1 proteins are an indicator of DNA damage whereas DNA polymerase- β plays a role in the repair of DNA strand breaks. Normal immortalised human pancreatic ductal epithelial (HPDE-6) cells remained unaffected by curcumin treatment. In addition, we also observed a significant increase in the phosphorylation of Chk1 at Ser-345, Cdc25C at Ser-216 and a subtle increase in ATM phosphorylation at Ser-1981. Concomitant decrease in the expressions of cyclin B1 and Cdk1 were seen in curcumin-treated cells. Further, curcumin treatment caused significant cleavage of caspase-3 and PARP in BxPC-3 but not in HPDE-6 cells. Silencing ATM/Chk1 expression by transfecting BxPC-3 cells with ATM or Chk1-specific SiRNA blocked the phosphorylation of ATM, Chk1 and Cdc25C and protected the cells from curcumin-mediated G2/M arrest and apoptosis. This study reflects the critical role of ATM/Chk1 in curcumin-mediated G2/M cell cycle arrest and apoptosis in pancreatic cancer cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Apoptosis - drug effects / Ataxia Telangiectasia Mutated Proteins / Biomedical and Life Sciences / Biomedicine / Cancer Research / Caspase 3 - drug effects / Caspase 3 - metabolism / Cell Cycle - drug effects / Cell Cycle Proteins - drug effects / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell Division - drug effects / Cell Line, Tumor / Checkpoint Kinase 1 / Collagen Type XI - drug effects / Collagen Type XI - metabolism / Curcumin - pharmacology / DNA Damage - drug effects / DNA-Binding Proteins - drug effects / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drug Resistance / Epidemiology / Gene Expression Regulation, Enzymologic - drug effects / Gene Expression Regulation, Neoplastic - drug effects / Gene Silencing - drug effects / Humans / Molecular Medicine / Oncology / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - enzymology / Pancreatic Neoplasms - pathology / Protein Kinases - drug effects / Protein Kinases - genetics / Protein Kinases - metabolism / Protein-Serine-Threonine Kinases - drug effects / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Transfection / Translational Therapeutics / Tumor Suppressor Proteins - drug effects / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism