Oncotarget

Research Papers:

CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations

Anchit Khanna, Jayant K. Rane, Kati K. Kivinummi, Alfonso Urbanucci, Merja A. Helenius, Teemu T. Tolonen, Outi R. Saramäki, Leena Latonen, Visa Manni, John E. Pimanda, Norman J. Maitland, Jukka Westermarck and Tapio Visakorpi _

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Oncotarget. 2015; 6:19661-19670. https://doi.org/10.18632/oncotarget.3875

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Abstract

Anchit Khanna1,2, Jayant K. Rane3, Kati K. Kivinummi1,4, Alfonso Urbanucci1,5,6, Merja A. Helenius1, Teemu T. Tolonen1, Outi R. Saramäki1, Leena Latonen1, Visa Manni1, John E. Pimanda2, Norman J. Maitland3, Jukka Westermarck7,8 and Tapio Visakorpi1

1 Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland

2 Adult Cancer Program, The Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW Medicine, University of New South Wales, Sydney, Australia

3 YCR Cancer Research Unit, Department of Biology, The University of York, Heslington, United Kingdom

4 Department of Signal Processing, Tampere University of Technology, Tampere, Finland

5 Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway

6 Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

7 Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland

8 Department of Pathology, University of Turku, Turku, Finland

Correspondence to:

Tapio Visakorpi, email:

Anchit Khanna, email:

Keywords: CIP2A, androgen receptor, castration-resistant prostate cancer, cancer stem-like cells

Received: December 30, 2014 Accepted: April 03, 2015 Published: April 19, 2015

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.


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