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.
Highlights
Prostate cancer is the most common male malignancy and the second leading cause of death for cancer in men of western Countries [1]
Both docetaxel resistant (DR)-Du145 and DR-PC3 cell variants have a consistently increased protein levels for prostate tumor overexpressed 1 (PTOV1) compared with parental docetaxel sensitive (DS) cells (Figure 1B and Supplementary Figure 1B), and a significant increase in RNA levels is observed in DR-Du145 but not in DR-PC3 cells (Figure 1C)
A significant increase in PTOV1 protein stability is detected in cycloheximide (CHX)-treated DR-Du145 cells, no significant differences were detected in DR-PC3 cells, suggesting that the mechanisms underlying the higher PTOV1 protein expression in DR cells need to be explored further (Supplementary Figure 2B)
Summary
Prostate cancer is the most common male malignancy and the second leading cause of death for cancer in men of western Countries [1]. Patients with metastatic prostate cancer undergo androgen deprivation therapy (ADT), very effective in reducing prostate tumor and metastatic growth. Progression to a castration-resistant prostate cancer (CRPC) eventually occurs [2, 3]. A taxol derived drug that prevents microtubule de-polymerization and mitotic division, was the standard treatment in US for CRPC patients until 2010 [4]. Docetaxel combined with androgen deprivation therapy have been used at earlier stages to improve the outcome for men with metastases at first www.impactjournals.com/oncotarget presentation [5,6,7], but in most cases it results in the development of a very aggressive resistant cancer
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