Is There Competition in Trafficking of VDAC-cored VRAC and SOC in NE Differentiation of Cells?

Abstract

The paper of Maruyama et al. (1) on ORAI1 in JBC on March 16, 2009 will stimulate research on additional components involved in SOCE (store-operated Ca2+ entry), as insinuated in the author's abstract. It can also be expected to raise endeavors concerning functional aspects of SOCE. A closer look at VDAC (voltage-dependent anion channel)-cored volume-regulated anion channel (VRAC) complexes (2) and SOCE in NE (neuroendocrine) differentiation of cancerous cells may be seminal in either direction. Concerning VRAC, already reported to be co-localized with SOC channels in LNCaP cells (3), methods and biomolecular means of the VDAC community are accessible. Concerning cancer, a direct involvement of ORAI1 and STIM1 was recently shown by RNA interference experiments (4). With regard to an involvement of VDAC in NE differentiation of cancerous cells recent data is worth considering: VDAC in cell membranes is involved in the RVD/AVD (regulatory volume decrease/apoptotic volume decrease) pathways via VDAC-cored VRAC complexes (2, 5); LNCaP cells under somatostatin up-regulate VDAC, probably a factor curbing progression to HRPC (hormone-refractory prostate cancer) (6); LNCaP cells on NE differentiation increase VRAC-based RVD and also endogenous ClC-3 (3), a putative VRAC modulator (2); RVD and apoptosis can be blocked by VRAC blockers (2, 5); correspondingly RVD of the LNCaP cell lines studied were inhibited by NPPB (5-nitro-2-(3-phenylpropylamino)benzoate) (3); crtl-LNCaP cells under thapsigargin and calcium showed about 50% IClswell reduction, while NE-LNCaP cells were almost unaffected, indicating the involvement of SOC channel regulation (3); under TNFα (tumor necrosis factor α) in normotonic surroundings the ctrl-LNCaP line, carrying less VRAC, showed a higher rate of inducible apoptosis as did its NE-differentiated form (3), which in either cell line further increased when NPPB was added; paradoxically, while anti-VDAC antibodies block staurosporine-induced apoptosis of cells by blocking VDAC-cored AVD (5), the RVD blocker NPPB enhances the apoptotic rate of either LNCaP cell line under the apoptotic stimulus of TNFα (3).