Abstract
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 Ca2+ homeostasis where the store-operated Ca2+ 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 Ca2+ 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.
Highlights
Neuroendocrine differentiation (NED) is a process which occurs in several types of carcinomas
We previously demonstrated that NED of LNCaP cells induced alterations in Ca2+ homeostasis including reduced filling of the endoplasmic reticulum (ER) Ca2+ store, decreased expression of the endolemmal SERCA 2b Ca2+ ATPase and the luminal Ca2+ binding calreticulin and down-regulated store-operated current (ISOC) [18]
The functional results obtained on NED-LNCaP cells were compared with regular androgen-dependent LNCaP cells (CT-LNCaP), which served as a control
Summary
Neuroendocrine differentiation (NED) is a process which occurs in several types of carcinomas. Prostatic carcinoma belongs to the tumours in which NED is suggested as an indicator of poor prognostic as the rate of NED of prostate cancer cells increases with the grade of the prostate cancer [1,2,3]. Androgen deprivation therapies cause prostate tumour regression. Such treatments become unsuccessful when PCa cells progress to an androgen-independent stage [4]. We and others have previously demonstrated that the androgendependent LNCaP
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