title: CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations.
abstract: Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients . CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired.These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer.
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.|Adult Cancer Program, The Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Anchit
authors.initials: A
authors.lastname: Khanna
authors.affiliation: YCR Cancer Research Unit, Department of Biology, The University of York, Heslington, United Kingdom.
authors.forename: Jayant K
authors.initials: JK
authors.lastname: Rane
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.|Department of Signal Processing, Tampere University of Technology, Tampere, Finland.
authors.forename: Kati K
authors.initials: KK
authors.lastname: Kivinummi
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.|Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.|Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Urbanucci
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Merja A
authors.initials: MA
authors.lastname: Helenius
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Teemu T
authors.initials: TT
authors.lastname: Tolonen
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Outi R
authors.initials: OR
authors.lastname: Saramäki
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Latonen
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Visa
authors.initials: V
authors.lastname: Manni
authors.affiliation: Adult Cancer Program, The Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW Medicine, University of New South Wales, Sydney, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.affiliation: YCR Cancer Research Unit, Department of Biology, The University of York, Heslington, United Kingdom.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Department of Pathology, University of Turku, Turku, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
authors.affiliation: Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen
keywords: CIP2A; androgen receptor; cancer stem-like cells; castration-resistant prostate cancer