title: A steroidal Na+/K+ ATPase inhibitor triggers pro-apoptotic signaling and induces apoptosis in prostate and lung tumor cells.
abstract: Recently we have reported potent anti-cancer actions of various steroidal Na(+)/K(+) ATPase inhibitors in multiple cell lines. Furthermore, the most powerful compound identified in this study, the 3-[(R)-3-pyrrolidinyl]oxime derivative (3-R-POD), was highly effective in various tumor cell lines in vitro, and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. In the present study we have addressed the molecular mechanisms implicated in the anti-cancer actions of 3-R-POD. We report here that 3-R-POD induces strong apoptotic responses in A549 lung- and in DU145 prostate- cancer cells. These effects are accompanied by significant upregulation of caspase-3 activity. Focussing on A549 cells, we further demonstrate late downregulation of BCL-2- and upregulation of c-Fos- gene transcription. In addition, the steroidal Na(+)/K(+) ATPase inhibitor induced late de-phosphorylation of Focal Adhesion Kinase (FAK) and activation of p38 MAPK. Our findings suggest that the steroidal Na(+)/K(+) ATPase inhibitor 3-R-POD induces apoptosis, paralleled by altered BCL-2 and c-Fos gene transcription, inhibition of the pro-survival FAK signalling, up-regulation of the pro-apoptotic p38 MAPK pathway and stimulation of caspase-3 activity.
authors.forename: Sabina
authors.initials: S
authors.lastname: Honisch
authors.forename: Saad
authors.initials: S
authors.lastname: Alkahtani
authors.forename: Michalis
authors.initials: M
authors.lastname: Kounenidakis
authors.forename: Guilai
authors.initials: G
authors.lastname: Liu
authors.forename: Saud
authors.initials: S
authors.lastname: Alarifi
authors.forename: Hamad
authors.initials: H
authors.lastname: Al-Yahya
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Dimas
authors.forename: Abdullah A
authors.initials: AA
authors.lastname: AlKahtane
authors.forename: Kyriakos C
authors.initials: KC
authors.lastname: Prousis
authors.forename: Bader
authors.initials: B
authors.lastname: Al-Dahmash
authors.forename: Theodora
authors.initials: T
authors.lastname: Calogeropoulou
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Alevizopoulos
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: Department of Biochemistry, University of Crete Medical School, GR-71110, Heraklion, Greece. cstourn@med.uoc.gr.
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D012263:Ribonucleosides / Q000494:pharmacology*; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D012263:Ribonucleosides; C069785:3-ribofuranosylpyrazolo(3,4-e)(1,3)oxazine-5,7-dione; D000254:Sodium-Potassium-Exchanging ATPase