Blockade of TRPC6 channels induced G2/M phase arrest and suppressed growth in human gastric cancer cells.
Channels formed by the canonical transient receptor potential (TRPC) subfamily of proteins are Ca(2+)-permeable, nonselective cation channels with various functions. Through a phospholipase C (PLC)-dependent mechanism TRPC6, a member of TRPC subfamily, can be activated by receptor tyrosine kinases (RTK) or G protein-coupled receptors (GPCR), which are implicated in cell proliferation and human malignancies. Here, we report that TRPC6 has a critical role in human gastric cancer development. Expression of TRPC6 was greatly upregulated in human gastric cancer epithelial cells compared with that in normal gastric epithelial cells. Treatment of AGS or MKN45 cells, human gastric cancer cell lines, with SKF96365, an agent known to inhibit TRPC channels, arrested cell cycle in G2/M phase and suppressed cell growth. Importantly, expressing a dominant negative mutant of TRPC6 (DNC6) in these cells also arrested cell cycle in G2/M phase and inhibited cell growth. The Ca(2+) elevation in the MKN45 cells evoked by histamine was inhibited by SKF96365 and DNC6. Moreover, inhibition of TRPC6 suppressed the formation of gastric tumors in nude mice. These results suggest that Ca(2+) elevation regulated by TRPC6 channels is essential for G2/M phase transition and for the development of gastric cancers.
Cai
Rong
R
Ruijin Hospital, Department of Radiochemotherapy, Shanghai Jiaotong University Medical School, China.
Ding
Xia
X
Zhou
Kechun
K
Shi
Yu
Y
Ge
Ruiliang
R
Ren
Gang
G
Jin
Yening
Y
Wang
Yizheng
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002455:Cell Division; D049109:Cell Proliferation; D004594:Electrophysiology; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000473:pathology / Q000517:prevention & control*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D000074287:TRPC6 Cation Channel
D002121:Calcium Channel Blockers; D007093:Imidazoles; D012333:RNA, Messenger; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; C492146:Trpc6 protein, mouse; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium