Remodeling of channel-forming ORAI proteins determines an oncogenic switch in prostate cancer

Cancer Cell. 2014 Jul 14;26(1):19-32. doi: 10.1016/j.ccr.2014.04.025. Epub 2014 Jun 19.

Abstract

ORAI 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 Ca(2+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy
  • Aged
  • Animals
  • Apoptosis
  • Arachidonic Acid / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cyclin D1 / metabolism
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress
  • Humans
  • Ion Channel Gating
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • Middle Aged
  • NFATC Transcription Factors / metabolism
  • Neoplasm Proteins / metabolism
  • ORAI1 Protein
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy
  • Protein Transport
  • RNA Interference
  • Stromal Interaction Molecule 1
  • Time Factors
  • Transfection
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • CCND1 protein, human
  • Calcium Channels
  • Membrane Proteins
  • NFATC Transcription Factors
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • Orai3 protein, human
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Cyclin D1
  • Arachidonic Acid