Differential role of transient receptor potential channels in Ca2+ entry and proliferation of prostate cancer epithelial cells.
One major clinical problem with prostate cancer is the cells' ability to survive and proliferate upon androgen withdrawal. Because Ca2+ is central to growth control, understanding the mechanisms of Ca2+ homeostasis involved in prostate cancer cell proliferation is imperative for new therapeutic strategies. Here, we show that agonist-mediated stimulation of alpha1-adrenergic receptors (alpha1-AR) promotes proliferation of the primary human prostate cancer epithelial (hPCE) cells by inducing store-independent Ca2+ entry and subsequent activation of nuclear factor of activated T cells (NFAT) transcription factor. Such an agonist-induced Ca2+ entry (ACE) relied mostly on transient receptor potential canonical 6 (TRPC6) channels, whose silencing by antisense hybrid depletion decreased both hPCE cell proliferation and ACE. In contrast, ACE and related growth arrest associated with purinergic receptors (P2Y-R) stimulation involved neither TRPC6 nor NFAT. Our findings show that alpha1-AR signaling requires the coupled activation of TRPC6 channels and NFAT to promote proliferation of hPCE cells and thereby suggest TRPC6 as a novel potential therapeutic target.
Thebault
Stephanie
S
Laboratoire de Physiologie Cellulaire, Institut National de la Sante et de la Recherche Medicale, Centre National de la Recherche Scientifique, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France. stephanie_thebault@yahoo.fr
Flourakis
Matthieu
M
Vanoverberghe
Karine
K
Vandermoere
Franck
F
Roudbaraki
Morad
M
Lehen'kyi
V'yacheslav
V
Slomianny
Christian
C
Beck
Benjamin
B
Mariot
Pascal
P
Bonnal
Jean-Louis
JL
Mauroy
Brigitte
B
Shuba
Yaroslav
Y
Capiod
Thierry
T
Skryma
Roman
R
Prevarskaya
Natalia
N
D000255:Adenosine Triphosphate / Q000494:pharmacology; D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011983:Receptors, Purinergic / Q000378:metabolism; D050052:TRPC Cation Channels / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D015854:Up-Regulation
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D011983:Receptors, Purinergic; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D050051:Transient Receptor Potential Channels; D010656:Phenylephrine; D000255:Adenosine Triphosphate; D002118:Calcium