Cytoskeleton Reorganization as an Alternative Mechanism of Store-Operated Calcium Entry Control in Neuroendocrine-Differentiated Cells

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.

ORAI channels are critical for receptor-mediated endocytosis of albumin

“…We found that the endocytosis of albumin in PTECs does not require the structural basis of F-actin, which is in agreement with an early study that cytochalasin D only reduced less than 5% of albumin uptake in opossum kidney epithelial cells 33 . We also showed that excessive F-actin has a negative impact on SOCE and albumin uptake, which is consistent with previous observations by us 16 and others 34 that excessive F-actin could act as a physical barrier between PM and ER, and thus block the interaction between STIM1 and ORAI channels and SOCE. The impairment of SOCE further leads to the reduction of albumin uptake in PTECs seen in the study.…”

Extracellular Vesicles in the Adaptive Process of Prostate Cancer during Inhibition of Androgen Receptor Signaling by Enzalutamide

“…Overexpression of calcium/calmodulin‐dependent kinase II is able to promote cell growth of LNCaP in androgen‐deprived conditions, suggesting crosstalk between the Ca 2+ dependent CaM and AR signalling axis . Further, the store‐operated Ca 2+ entry (SOCE) event, which is regulated by the SOC channels and induced by F‐actin polymerization, has been shown to allow neuroendocrine type prostate cancer to escape apoptosis . As such, Ca 2+ supplementation for advanced prostate cancer patients under ADT and experiencing osteoporosis has been assessed in the clinical setting .…”

“…[37] Further, the store-operated Ca 2+ entry (SOCE) event, which is regulated by the SOC channels and induced by F-actin polymerization, has been shown to allow neuroendocrine type prostate cancer to escape apoptosis. [38] As such, Ca 2+ supplementation for advanced prostate cancer patients under ADT and experiencing osteoporosis has been assessed in the clinical setting. [39] Our data have shown that treatment with ENZ does not inhibit the secretion of EVs and alters the sorting of Ca 2+ -regulated proteins into EVs.…”

RPGR protein complex regulates proteasome activity and mediates store-operated calcium entry

“…The actin cytoskeleton plays an important role in SOCE. It has been shown that disruption of the actin cytoskeleton using Cytochalsin D or latrunculin A significantly decreased SOCE in platelets, endothelial cells, type I astrocytes, glioma C6 cells and pancreatic acinar cells [ 36 , 58 , 59 ]. By contrast, inhibition of actin polymerization in NIH 3T3, DDT1MF-2 or A7r5 cells did not modify SOCE [ 36 ].…”