Carcinogenesis Advance Access originally published online on January 28, 2009
Carcinogenesis 2009 30(5):737-744; doi:10.1093/carcin/bgp034
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ATP-sensitive potassium channels control glioma cells proliferation by regulating ERK activity
Department of Occupational Health and Occupational medicine, School of Public Health and Tropical Medicine
1 Department of Neurobiology
2 Neuromedicine Institute, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
* To whom correspondence should be addressed. Tel: +86 20 6164 8301; Fax: +86 20 6164 8301; Email: lihuang{at}fimmu.com
Ion channels are found in a variety of cancer cells and necessary for cell cycle and cell proliferation. The roles of K+ channels in the process are, however, poorly understood. In the present study, we report that adenosine triphosphate (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 small interfering RNA (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 of tumor in nude mice 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 extracellular signal-regulated kinase (ERK) activation. We found that activating KATP channel triggered ERK activation and inhibiting KATP channel depressed ERK activation. U-0126, the mitogen-activated protein kinase kinase (MAPK kinase) 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 that KATP channels control glioma cell proliferation via regulating ERK pathway. We concluded that KATP channels are important in pathological cell proliferation and open a promising pathway for novel targeted therapies.
Abbreviations: ATP, adenosine triphosphate; ERK, extracellular signal-regulated kinase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; MAPK, mitogen-activated protein kinase kinase; MEK, mitogen-activated kinase kinase; MTT, Methyl-thiazolyl-tetrazolium; PBS, phosphate-buffered saline; siRNA, small interfering RNA; SUR, sulfonylurea receptor
These authors contributed equally to this work. Received October 14, 2008; revised January 14, 2009; accepted January 24, 2009.