Cytoskeleton reorganization as an alternative mechanism of store-operated calcium entry control in neuroendocrine-differentiated cells.
Neuroendocrine differentiation (NED) is a hallmark of advanced androgen-independent prostate cancer, for which no successful therapy exists. NED tumour cells escape apoptotic cell death by alterations of Ca(2+) homeostasis where the store-operated Ca(2+) entry (SOCE) is known to be a key event. We have previously shown that the downregulation of Orai1 protein representing the major molecular component of endogenous SOCE in human prostate cancer cells, and constituting the principal source of Ca(2+) influx used by the cell to trigger apoptosis, contributes to the establishment of an apoptosis-resistant phenotype (Cell Death Dis. 2010 Sep 16;1:e75.). Here, we report for the first time that the decrease of SOCE during NED may be caused by alternative NED-induced mechanism involving cytoskeleton reorganisation. NED induced by androgen deprivation resulted in a decrease of SOCE due to cortical F-actin over-polymerization which inhibits thapsigargin-induced SOCE. The disruption of F-actin polymerization by Cytochalasin D in NED cells restored SOCE, while the induction of F-actin polymerization by jasplakinolide or calyculin A diminished SOCE without changing the expression of key SOCE players: Orai1, STIM1, and TRPC1. Our data suggest that targeting cytoskeleton-induced pathways of malignant cells together with SOCE-involved channels may prove a useful strategy in the treatment of advanced prostate cancer.
Inserm, U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, France.
Karine
K
Vanoverberghe
V'yacheslav
V
Lehen'kyi
Stéphanie
S
Thébault
Maylis
M
Raphaël
Fabien
F
Vanden Abeele
Christian
C
Slomianny
Pascal
P
Mariot
Natalia
N
Prevarskaya
D000199:Actins / Q000378:metabolism; D000728:Androgens / Q000378:metabolism; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D008297:Male; D008387:Marine Toxins; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D055099:Neuroendocrine Cells / Q000166:cytology*; D000071740:ORAI1 Protein; D010080:Oxazoles / Q000494:pharmacology; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000628:therapy; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000378:metabolism
D000199:Actins; D000728:Androgens; D015220:Calcium Channels; D017931:DNA Primers; D008387:Marine Toxins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D010080:Oxazoles; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D015638:Cytochalasin D; C059041:calyculin A; D002118:Calcium