Store-operated Ca2+ channels in prostate cancer epithelial cells: function, regulation, and role in carcinogenesis.
Ca2+ homeostasis mechanisms, in which the Ca2+ entry pathways play a key role, are critically involved in both normal function and cancerous transformation of prostate epithelial cells. Here, using the lymph node carcinoma of the prostate (LNCaP) cell line as a major experimental model, we characterize prostate-specific store-operated Ca2+ channels (SOCs)--a primary Ca2+ entry pathway for non-excitable cells--for the first time. We show that prostate-specific SOCs share major store-dependent, kinetic, permeation, inwardly rectifying, and pharmacological (including dual, potentiation/inhibition concentration-dependent sensitivity to 2-APB) properties with "classical" Ca2+ release-activated Ca2+ channels (CRAC), but have a higher single channel conductance (3.2 and 12pS in Ca2+- and Na+-permeable modes, respectively). They are subject to feedback inhibition via Ca2+-dependent PKC, CaMK-II and CaM regulatory pathways and are functionally dependent on caveolae integrity. Caveolae also provide a scaffold for spatial co-localization of SOCs with volume-regulated anion channels (VRAC) and their Ca2+-mediated interaction. The TRPC1 and TRPV6 members of the transient receptor potential (TRP) channel family are the most likely molecular candidates for the formation of prostate-specific endogenous SOCs. Differentiation of LNCaP cells to an androgen-insensitive, apoptotic-resistant neuroendocrine phenotype downregulates SOC current. We conclude that prostate-specific SOCs are important determinants in the transition to androgen-independent prostate cancer.
Vanden Abeele
F
F
Laboratoire de Physiologie Cellulaire, INSERM EMI 0228, Bâtiment SN3, USTL, 59655 Villeneuve d'Ascq, France.
Shuba
Y
Y
Roudbaraki
M
M
Lemonnier
L
L
Vanoverberghe
K
K
Mariot
P
P
Skryma
R
R
Prevarskaya
N
N
D015415:Biomarkers; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007700:Kinetics; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000187:drug effects; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; D014407:Tumor Cells, Cultured
D015415:Biomarkers; D015220:Calcium Channels; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C120776:TRPV6 channel; C096351:transient receptor potential cation channel, subfamily C, member 1; D002118:Calcium