Increased K+ efflux and apoptosis induced by the potassium channel modulatory protein KChAP/PIAS3beta in prostate cancer cells.
K(+) channel-associated protein/protein inhibitor of activated STAT (KChAP/PIAS3beta) is a potassium (K(+)) channel modulatory protein that boosts protein expression of a subset of K(+) channels and increases currents without affecting gating. Since increased K(+) efflux is an early event in apoptosis, we speculated that KChAP might induce apoptosis through its up-regulation of K(+) channel expression. KChAP belongs to the protein inhibitor of activated STAT family, members of which also interact with a variety of transcription factors including the proapoptotic protein, p53. Here we report that KChAP induces apoptosis in the prostate cancer cell line, LNCaP, which expresses both K(+) currents and wild-type p53. Infection with a recombinant adenovirus encoding KChAP (Ad/KChAP) increases K(+) efflux and reduces cell size as expected for an apoptotic volume decrease. The apoptosis inducer, staurosporine, increases endogenous KChAP levels, and LNCaP cells, 2 days after Ad/KChAP infection, show increased sensitivity to staurosporine. KChAP increases p53 levels and stimulates phosphorylation of p53 residue serine 15. Consistent with activation of p53 as a transcription factor, p21 levels are increased in infected cells. Wild-type p53 is not essential for induction of apoptosis by KChAP, however, since KChAP also induces apoptosis in DU145 cells, a prostate cancer cell line with mutant p53. Consistent with its proapoptotic properties, KChAP prevents growth of DU145 and LNCaP tumor xenografts in nude mice, indicating that infection with Ad/KChAP might represent a novel method of cancer treatment.
Wible
Barbara A
BA
Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109, USA. bwible@metrohealth.org
Wang
Liming
L
Kuryshev
Yuri A
YA
Basu
Aruna
A
Haldar
Subrata
S
Brown
Arthur M
AM
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000494:pharmacology*; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT; D019311:Staurosporine / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D016159:Tumor Suppressor Protein p53; D019311:Staurosporine; D011188:Potassium