Carcinogenesis Advance Access published online on January 28, 2009
Carcinogenesis, doi:10.1093/carcin/bgp034
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ATP-sensitive Potassium Channels Control Glioma Cells Proliferation by Regulating ERK Activity
a School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
b Department of Neurobiology, Southern Medical University, Guangzhou, Guangdong 510515, China
c Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
* Corresponding author. Tel.: +86-20-6164-8301; fax: +86-20-6164-8301.e-mail address: lihuang{at}fimmu.com (F. Zou).
Ion channels are found in a variety of cancer cells and necessary for cell cycle and cell proliferation. The role(s) of K+ channels in the process is, however, poorly understood. In the present study, we report ATP-sensitive potassium channel activity plays a critical role in the proliferation of glioma cells. The expression of KATP channels in glioma tissues was greatly increased than that in normal tissues. Treatment of glioma cells with tolbutamide, KATP channels inhibitor, suppressed the proliferation of glioma cells and blocked glioma cell cycle in G0/G1 phase. Similarly, downregulation of KATP channels by siRNA inhibited glioma cell proliferation. On the other hand, KATP channels agonist diazoxide and overexpression of KATP channels promoted the proliferation of glioma cells. Moreover, inhibiting KATP channels slowed the formation in nude mice of tumor generated by injection of glioma cells. Whereas activating KATP channels promoted development of tumor in vivo. The effect of KATP channels activity on glioma cells proliferation is mediated by ERK activation. We found that activating KATP channel triggered ERK activation and inhibiting KATP channel depressed ERK activation. U-0126, the MEK inhibitors blocked ERK activation and cell proliferation induced by diazoxide. Furthermore, constitutively activated MEK plasmids transfection reversed the inhibitory effects of tolbutamide on glioma proliferation, lending further support for a role of ERK in mediating this process. Our results suggest KATP channels control glioma cell proliferation via regulating ERK pathway. We concluded KATP channels are important in pathological cell proliferation and open a promising pathway for novel targeted therapies.
1 These authors made an equal contribution to this paper.
Received October 14, 2008; revised January 14, 2009; accepted January 24, 2009.