Endoplasmic reticulum Ca(2+) content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor contributes to prostate cancer cell resistance to androgen deprivation.

Benoît Boutin (1) , Nicolas Tajeddine (1) , Giovanni Monaco (2) , Jordi Molgó (3, 4) , Didier Vertommen (1) , Mark Rider (1) , Jan B Parys (2) , Geert Bultynck (2) , Philippe Gailly (1)

1 UCL - Université Catholique de Louvain = Catholic University of Louvain
2 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
3 N&eD - Neurobiologie et Développement
4 INAF - Institut de Neurobiologie Alfred Fessard

Reference treatment of advanced prostate cancer (PCa) relies on pharmacological or surgical androgen deprivation therapy. However, it is only temporarily efficient as tumor cells inevitably adapt to the low testosterone environment and become hormone-refractory (HRPCa). We observed that androgen removal in HRPCa-derived LNCaP cells causes different alterations in their Ca(2+) homeostasis among which a reduction of ER Ca(2+) content. We show that the decrease in [Ca(2+)]ER is due to a modest overexpression of type 1 IP3R and a threefold increased phosphorylation of IP3R1 on Ser-1716, a protein kinase A (PKA) consensus site, both implicated in ER Ca(2+) leak. Accordingly, ER Ca(2+) content was restored by siRNA-mediated down-regulation of IP3R1 or by inhibition of its phosphorylation by competition with a permeant TAT-peptide containing the Ser-1716 consensus phosphorylation sequence or by treatment with the PKA inhibitor H89. Moreover, inhibition of the IP3R1 phosphorylation by both methods sensitized the LNCaP cells to androgen deprivation-induced apoptosis. In addition, SERCA2b overexpression precluded the effect of androgen deprivation on ER Ca(2+) store content and reduced resistance to androgen deprivation. Taken together, these results indicate that lowering the ER Ca(2+)-store content by increasing IP3R1 levels and IP3R1 phosphorylation by PKA is a protective mechanism by which HRPCa-derived cells escape cell death in the absence of androgenic stimulation.

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Urologie et Néphrologie

Benoît Boutin, Nicolas Tajeddine, Giovanni Monaco, Jordi Molgó, Didier Vertommen, et al.. Endoplasmic reticulum Ca(2+) content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor contributes to prostate cancer cell resistance to androgen deprivation.. Cell Calcium, 2015, 57 (4), pp.312-20. ⟨10.1016/j.ceca.2015.02.004⟩. ⟨hal-01165614⟩