Abstract
Impaired Ca2+ signaling in prostate cancer contributes to several cancer hallmarks, such as enhanced proliferation and migration and a decreased ability to induce apoptosis. Na+ influx via transient receptor potential melastatin 4 channel (TRPM4) can reduce store-operated Ca2+ entry (SOCE) by decreasing the driving force for Ca2+. In patients with prostate cancer, gene expression of TRPM4 is elevated. Recently, TRPM4 was identified as a cancer driver gene in androgen-insensitive prostate cancer.We investigated TRPM4 protein expression in cancer tissue samples from 20 patients with prostate cancer. We found elevated TRPM4 protein levels in prostatic intraepithelial neoplasia (PIN) and prostate cancer tissue compared to healthy tissue. In primary human prostate epithelial cells (hPEC) from healthy tissue and in the androgen-insensitive prostate cancer cell lines DU145 and PC3, TRPM4 mediated large Na+ currents. We demonstrated significantly increased SOCE after siRNA targeting of TRPM4 in hPEC and DU145 cells. In addition, knockdown of TRPM4 reduced migration but not proliferation of DU145 and PC3 cells. Taken together, our data identify TRPM4 as a regulator of SOCE in hPEC and DU145 cells, demonstrate a role for TRPM4 in cancer cell migration and suggest that TRPM4 is a promising potential therapeutic target.
Highlights
In prostate cancer, decreased store-operated Ca2+ entry (SOCE) signals contribute to several hallmark functions of cancer, such as increased proliferation and migration and a reduction in the ability to induce apoptosis [1,2,3,4]
We demonstrated significantly increased SOCE after Small interfering RNA transfection (siRNA) targeting of transient receptor potential melastatin 4 channel (TRPM4) in human prostate epithelial cells (hPEC) and DU145 cells
Cell migration depends on intracellular Ca2+ and lately the spatial and temporal organisation of STIM/ Orai dependent Ca2+ gradients has been revealed [4648]
Summary
In prostate cancer, decreased store-operated Ca2+ entry (SOCE) signals contribute to several hallmark functions of cancer, such as increased proliferation and migration and a reduction in the ability to induce apoptosis [1,2,3,4]. The molecular key players of SOCE are STIM1 (stromal interaction molecule 1) in the membrane of intracellular Ca2+ stores and Orai Ca2+ channels in the plasma membrane. STIM1 proteins cluster and recruit Orai Ca2+ channels, which subsequently mediate SOCE [7, 8]. STIM/Oraiwww.impactjournals.com/oncotarget mediated Ca2+ signaling contributes to cell migration in different types of cancer, including melanoma [9, 10], glioblastoma [11, 12], renal carcinoma [13], hepatocarcinoma [14], breast cancer [15, 16], cervical cancer [17], and prostate cancer [18]
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