Remodeling of Channel-Forming ORAI Proteins Determines an Oncogenic Switch in Prostate Cancer

• Disrupted dynamic equilibrium of ORAI channels determines cancer cell phenotype
• Microenvironment perturbations induce ORAI1/3 association and Ca2+ entry remodeling
• ORAI1/3 heteromers promote proliferation by arachidonic acid-mediated Ca2+ entry
• The ORAI3 oncogenic switch represents a therapeutic target in prostate cancer

SummaryORAI family channels have emerged as important players in malignant transformation, yet the way in which they reprogram cancer cells remains elusive. Here we show that the relative expression levels of ORAI proteins in prostate cancer are different from that in noncancerous tissue. By mimicking ORAI protein remodeling observed in primary tumors, we demonstrate in in vitro models that enhanced ORAI3 expression favors heteromerization with ORAI1 to form a novel channel. These channels support store-independent Ca2+ entry, thereby promoting cell proliferation and a smaller number of functional homomeric ORAI1-based store-operated channels, which are important in supporting susceptibility to apoptosis. Thus, our findings highlight disrupted dynamic equilibrium of channel-forming proteins as an oncogenic mechanism.

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