Prostate Tumor Overexpressed-1 (PTOV1) promotes docetaxel-resistance and survival of castration resistant prostate cancer cells

// Veronica Canovas 1 , Yolanda Punal 1 , Valentina Maggio 1 , Enric Redondo 1 , Mercedes Marin 2 , Begona Mellado 2 , Mireia Olivan 1 , Matilde Lleonart 3 , Jacques Planas 1, 4 , Juan Morote 1, 4 and Rosanna Paciucci 1 1 Biomedical Research Group of Urology, Vall d’Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain 2 Laboratory of Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Medical Oncoloy Department, Hospital Clinic, Barcelona, Spain 3 Biomedical Research in Cancer Stem Cells, Vall d’Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain 4 Deparment of Urology, Vall d’Hebron Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain Correspondence to: Rosanna Paciucci, email: rosanna.paciucci@vhir.org Keywords: PTOV1, docetaxel resistance, prostate cancer, metastasis, apoptosis Received: November 09, 2016     Accepted: June 19, 2017     Published: July 22, 2017 ABSTRACT Metastatic prostate cancer is presently incurable. The oncogenic protein PTOV1, first described in prostate cancer, was reported as overexpressed and significantly correlated with poor survival in numerous tumors. Here, we investigated the role of PTOV1 in prostate cancer survival to docetaxel and self-renewal ability. Transduction of PTOV1 in docetaxel-sensitive Du145 and PC3 cells significantly increased cell survival after docetaxel exposure and induced docetaxel-resistance genes expression ( ABCB1, CCNG2 and TUBB2B ). In addition, PTOV1 induced prostatospheres formation and self-renewal genes expression ( ALDH1A1, LIN28A, MYC and NANOG ). In contrast, Du145 and PC3 cells knockdown for PTOV1 significantly accumulated in the G2/M phase, presented a concomitant increased subG1 peak, and cell death by apoptosis. These effects were enhanced in docetaxel-resistant cells. Analyses of tumor datasets show that PTOV1 expression significantly correlated with prostate tumor grade, drug resistance ( CCNG2 ) and self-renewal ( ALDH1A1, MYC ) markers. These genes are concurrently overexpressed in most metastatic lesions. Metastases also show PTOV1 genomic amplification in significant co-occurrence with docetaxel-resistance and self-renewal genes. Our findings identify PTOV1 as a promoter of docetaxel-resistance and self-renewal characteristics for castration resistant prostate cancer. The concomitant increased expression of PTOV1 , ALDH1A1 and CCNG2 in primary tumors, may predict metastasis and bad prognosis.