Abstract 3037: Role of KCNN4 in ovarian cancer and its pharmacologic activation increases sensitivity to cisplatin
Authors: Yutaka Shoji, GVR Chandramouli, Deepak Nagendra, Vinay K. Valluru, John I. Risinger
Journal: Cancer Research (2011)

Abstract Ovarian cancer is the second most common and most lethal gynecologic cancer in the United States with an estimated 15520 deaths expected from 21,650 cases. Patients with stage I disease have a relatively favorable survival approaching 80%, however most patients are first diagnosed with stage III and IV metastatic disease and have very poor prognosis. Expression of potassium channel genes has been shown to affect chemosensitivity and cell proliferation in several tumor types. We examined the expression of the known potassium channel genes in ovarian cancer and the presumptive cells of ovarian cancer origin. Affymetrix U133 Plus2.0 array data identified that the KCNN4 gene was up-regulated in 15 of 20 stage IIIC or IV serous ovarian cancers compared to eight cases of normal ovarian surface epithelium. This result was confirmed by quantitative real-time polymerase chain reactions (qRT-PCR) using an independent set of 25 ovarian cancers compared to 10 normals. Also, we assessed expression of KCNN4 in a large set (101 ovarian cases) of publically available microarray data (Berchuck, et al. Clin Cancer Res, 2009) and normal fallopian tube. These data confirmed that KCNN4 was highly-expressed in ovarian cancer and also showed expression in normal fallopian tube epithelial cells -the other suspected candidate for the cell of origin of ovarian cancers. KCNN4 forms the intermediate conductance Ca2+ – activated K+ channel (IKCa channel), which serves as a highly sensitive environmental sensor of intracellular calcium. Studies in other tumor types suggest that potassium channels are integral components of cellular proliferation. siRNA and shRNA mediated knockdown of KCNN4 resulted in decreased cell proliferation in cell culture models of ovarian cancer suggesting an essential role for KCNN4 in ovarian cancer cell growth and viability. Furthermore we hypothesized that by pharmacologically activating these channels we could further increase the killing of ovarian cancer cells by cis-platinum. We found that 9 of 11 ovarian cancer cell lines demonstrated functionally active IKCa channels and we were able to increase the sensitivity of these cells to cis-platinum following IKCa channel activation with 1-EBIO -a specific activator of IKCa channels. The chemo-sensitizing effect of treating these cells with the activator was reversed by adding clotrimazole -a specific inhibitor of the IKCa channels, further suggesting this effect was mediated through KCNN4. Furthermore, co-treatment of 1-EBIO and a non-lethal dose of cis-platinum to OVCAR5 cells resulted in apoptotic cell death suggesting a chemo-sensitizing role for IKCa channels. Preliminary data in vivo mimic some of the in vitro results. Our data shows that KCNN4 is integral to ovarian cancer cell growth and that sensitization with pharmacologic activators such as 1-EBIO may have future therapeutic benefit for increasing cancer cell sensitivity to chemotherapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3037. doi:10.1158/1538-7445.AM2011-3037