Potassium channels in prostate and colonic cancer

Large conductance Ca2+-activated K+ channels in human prostate cancer The KCNMA1 gene encoding the alpha-subunit of BK channels is amplified and BK channel expression is enhanced in late-stage, metastatic and hormone-refractory human prostate cancer tissues, whereas benign prostate tissues show only a weak expression of BK channels. PC-3 hormone-insensitive prostate cancer cells, but not hormone-sensitive prostate cancer cells (LNCaP) and benign prostate hyperplasia cells (BPH-1), show an amplification of the KCNMA1 gene and enhanced expression for BK channels. BK channel blockers and siRNA inhibit currents and growth of PC-3 cells. The BK channel activator 17beta-estradiol do not further stimulate currents or cell proliferation in PC-3 cells, indicating maximal channel activity and hormone insensitivity of the cells. On the contrary, 17beta-estradiol significantly enhances both currents and proliferation in LNCaP and BPH-1 cells. These results establish a role of BK channels for proliferation of prostate cancer cells. BK channel expression in late stage prostate cancer may be used as a prognostic marker and appears as a promising target for diagnosis and therapy of prostate cancer. Potassium channels in colonic cancer The role of K+ channels for proliferation of colonic cancer is shown in T84 human colonic carcinoma cells, mouse colorectal cancer models. Abnormal colonic histology in cancer mouse models At early stages of dimethylhydrazine (DMH) and N-methy-N-nitrosourea (MNU) treatment, histology demonstrated inflammation of the mouse colon. At later stage of carcinogen administration, changes of mucosal architecture and dysplasia were clearly observable. Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are found in almost all human colonic cancers, and in familiar adenomatous polyposis. Heterozygous APCMin/+ mice developed multiple intestinal neoplasias. Changes in Na+ and Cl- transport in colonic cancer mouse models. Initial DMH or MNU treatment decreased Na+ and Cl- transport in the colon, which was also detected in the inflamed DSS-colon. Reduced Na+ absorption and Cl- secretion in the inflamed colon are probably a result of reduced Na+/K+ ATPase activity. In contrast to carcinogen treated mice, ENaC currents and expression are increased in the colon of APCMin/+ mice. Taken together, inflammation reduces Na+ absorption and promotes diarrhea, which is often observed during colitis. Conversely, colonic polyposis is often accompanied by stool irregularities. The increase in colonic Na+ absorption in APCMin/+ mice may contribute to dehydration of the feces and constipation. Pathological expression of K+ channels in the colonic epithelium We demonstrated a role of Kv and BK channels for development of colonic cancer both in vitro and in vivo. In T84 cells, we detected molecular and functional expression of several types of K+ channels, but only Kv support proliferation. These channels assist in regulation of intracellular pH and cellular Ca2+ signaling. We also found that Kv1.3, Kv1.5, Kv3.1 and members of the EAG-family are enhanced in the premalignant colon induced by carcinogens. In the APCMin/+ model, EAG and BK channels are increased in the proximal and distal colon, respectively. Eag-1 and BK expression in human colorectal and prostate carcinomas Expression of Eag-1 channels is detected in colonic crypts from patients with colorectal carcinomas, but in the healthy colons. The Eag-1 gene is amplified in human colonic cancers and is associated with reduced overall survival of the patients. This may serves as an early diagnostic and prognostic marker for cancer patients. Taken together, evidence is presented for a role of K+ channels during development and growth of prostate and colonic cancer. Kv channels, particularly Eag-1, and BK channels support proliferation and are likely to support progression of premalignant tissues towards cancer. Both BK and Eag-1 are markers of adverse prognosis in patients. The present data may therefore be useful in improving diagnosis, and treatment, and may have a prognostic value in patients with prostate and colonic cancer.