Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression.
Curcumin (diferuloylmethane), is a natural chemopreventive agent known to inhibit the proliferation of several cancer cell lines. It has been previously demonstrated that curcumin is a potent inhibitor of EGF-receptor (EGFR) tyrosine kinase, but its inhibitive effect on p21-activated kinase 1 (PAK1), a downstream protein of EGFR, has not been defined. In this paper we found that curcumin repressed the expression of HER2 and inhibited the kinase activity of PAK1 without affecting its expression. Silencing HER2 in gastric cancer cells showed that even if PAK1 activity was transiently strengthened by EGF, curcumin still had a strong inhibitive effect. It should be emphasized that kinase assay in vitro showed that curcumin could act as an ATP-competitive inhibitor, which was supported by computer-aided molecular modeling. Curcumin also downregulated the mRNA and the protein expression of cyclin D1 and suppressed transition of the cells from G(1) to S phase. Therefore, curcumin inhibited the proliferation and invasion of gastric cancer cells. Overall, these results provided novel insights into the mechanisms of curcumin inhibition of gastric cancer cell growth and potential therapeutic strategies for gastric cancer.
Cai
Xin-Ze
XZ
Department of Cell Biology, Key Laboratory of Cell Biology of Ministry of Public Health of China, China Medical University, Shenyang, China.
Wang
Jian
J
Li
Xiao-Dong
XD
Wang
Gui-Ling
GL
Liu
Fu-Nan
FN
Cheng
Mao-Sheng
MS
Li
Feng
F
D000230:Adenocarcinoma / Q000473:pathology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018734:Genes, erbB-2 / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000473:pathology*; D054462:p21-Activated Kinases / Q000096:biosynthesis* / Q000235:genetics
D016588:Anticarcinogenic Agents; D003474:Curcumin; D019938:Cyclin D1; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D054462:p21-Activated Kinases; C530104:CCND1 protein, human; C508053:ERBB2 protein, human; C515903:PAK1 protein, human