HERG Channel-mediated Tumor Cell Proliferation Inhibition And Apoptosis

Background and aim:Voltage-gated potassium channels play key roles in differentiation and growth of cells. The understanding of the molecular mechanisms underlying cell in human tumor such as colon cancers could provide not only more sensitive prognostic analyses but also novel molecular targets for cancer therapy. Inhibition of these channels is also known to suppress proliferation of cells. To investigate the effects on the proliferation of the human ether-a-go-go related gene (HERG) K+ channel highly expressing cancer cells. HERG is believe to have an unusually large inner cavity due to the absence of two praline residues in S6 (present in other such channels) that produce a "kink" in that region of the Kv proteins’structure,the resulting putative increase in capacity within HERG’s pore cavity is thought to explain the "promiscuity" of the channel. The HERG potassium channel might have a non-canonical drug binding site, distinct from the channel’s inner cavity, that could be responsible for elements of closed-state pharmacological inhibition of the channel. HERG channel activity modulates the progression through the mitotic cycle, and mainly expressed during the S phase of the cell cycle. On the whole, HERG channels may play a prominent role in the control of tumor cell proliferation and apoptosis. HERG protein is expressed in a high percentage of primary human colorectal cancers, whereas no expression could be detected either in normal colonic mucosa or in adenomas.HERG are involved in activation and proliferation and is proposed as a novel diagnostic and prognostic factor in human cancers as well as a target for therapy.Methods:Human colon cancer HT-29 cells were grown with routine cell cultivation.The specific blocker erythromycin for HERG channels was used.Cells were treated with different concentration of erythromycin. MTT was used to detect activity of erythromycin on colon cancer cell HT-29. Flow cytometry analysis indicates that inhibition of HERG channels increases apoptosis of cells. Through western blotting we assess the association between HERG protein expression and apoptosis factors such as Bax,P53.χ2 test was used to identify drug’s dose-apoptosis relation in the flow cytometry.Results:Erythromycin significantly reduced proliferation of colon cancer cell HT-29from the MTT experiment.The drug doses increase, and cell apoptosis rise. Apoptosis and decreased invasiveness was induced, expression level of hERG protein was downregulated, p53 and Bax protein were upregulated in a dose-dependent manner in erythromycin-treated HT-29 cells.Conclusion:The study demonstrates that HERG potassium channels are blocked by erythromycin.The inhibition of erythromycin is in a dose-dependent manner.We conclude that HERG protein is involved in carcinogenesis of colon cancer and is a potential therapeutic target of colon cancer.