Alterations in atp-dependence ofswelling- activated cl- currentassociated with neuroendocrinedifferentiation of lncap prostatecancer epithelial cells
R.M. Lazarenko, A.P. KondratskyN.Ch. Pogorela, Y.M. Shuba
A.A.Bogomoletz Institute of Physiology, National Academy ofScience of Ukraine, Kyiv
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Abstract
Increasing population of malignant, apoptosis resistant
neuroendocrine (NE) cells due to differentiation of prostate
epithelial/basal cells is a hallmark of advanced, androgen-inde-
pendent prostate cancer, for which there is no successful
therapy. Acquisition of apoptosis resistance involves alter-
ations in the mechanisms of cell volume homeostasis, of which
volume-regulate anion channels (VRAC) that carry swelling-
activated Cl- current (ICl,swell) represent one of the key determi-
nants. Given that VRAC function is generally known to be
ATP-dependent, here we investigated how such dependence
may evolve during NE differentiation of LNCaP prostate cancer
epithelial cells. In the whole-cell patch-clamp recording mode
ICl,swell could be activated in response to hypotonicity-induced
cell swelling in control and NE-differentiated (by incubation in
membrane-permeable cAMP analogs) LNCaP cells even fol-
lowing total depletion of intracellular ATP using a cocktail of
metabolic inhibitors. However, this basal ICl,swell had about
30% higher density and was less inactivating in NE-differenti-
ated cells. Inclusion of 5 mM Mg-ATP in the patch pipette
caused ICl,swell augmentation in both cell types. The augmenta-
tion in the control cells was more prominent and occurred
mostly at the expense of a non-inactivating current component.
We conclude that ICl,swell in LNCaP cells consists of a non-
inactivating, ATP-dependent and inactivating, ATP-indepen-
dent components. NE differentiation promotes the increase of
non-inactivating component and partial loss of its ATP sensi-
tivity making the whole ICl,swell less ATP-sensitive as well. By
largely avoiding the ATP metabolic control ICl,swell may contrib-
ute to better control of cell volume under metabolic stress and
thus enhance the survival rates of apoptosis-resistant NE cells.
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