Abstract
Simple SummaryTherapeutic options for the treatment of men with metastatic castration-resistant prostate cancer are limited. Docetaxel—a taxane-based chemotherapeutic agent—was the first treatment to demonstrate significant efficacy in the treatment of this disease. However, responses to docetaxel are frequently curtailed by development of drug resistance, and patients eventually succumb to disease progression due to acquisition of drug resistance. In this study, we established drug-resistant prostate cancer cell lines and identified several mechanisms that may be associated with the development of drug resistance in prostate cancer. Actioning these mechanisms could provide a potential approach to re-sensitize drug-resistant cancer cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with metastatic castration-resistant prostate cancer.Docetaxel—a taxane-based chemotherapeutic agent—was the first treatment to demonstrate significant improvements in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, the response to docetaxel is generally short-lived, and relapse eventually occurs due to the development of resistance. To explore the mechanisms of acquired docetaxel resistance in prostate cancer (PCa) and set these in the context of androgen deprivation therapy, we established docetaxel-resistant PCa cell lines, derived from the androgen-dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line. We generated two docetaxel-resistant LNCaPR and C4-2BR sub-lines, with IC50 values 77- and 50-fold higher than those of the LNCaP and C4-2B parental cells, respectively. We performed gene expression analysis of the matched sub-lines and found several alterations that may confer docetaxel resistance. In addition to increased expression of ABCB1, an ATP-binding cassette (ABC) transporter, and a well-known gene associated with development of docetaxel resistance, we identified genes associated with androgen signaling, cell survival, and overexpression of ncRNAs. In conclusion, we identified multiple mechanisms that may be associated with the development of taxane drug resistance in PCa. Actioning these mechanisms could provide a potential approach to re-sensitization of docetaxel-resistant PCa cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with mCRPC.
Highlights
Prostate cancer (PCa) is the most common cancer among men in developed countries and a major cause of male mortality, mostly due to disease progression to metastatic castration-resistant prostate cancer [1,2]
Given the discordance between androgen receptor (AR) mRNA and AR protein levels previously observed Given the discordance between AR mRNA and AR protein levels previously obin LNCaP cells [23], and since AR protein degradation is a key regulatory mechanism served in LNCaP cells [23], and since AR protein degradation is a key regulatory mechain prostate epithelial cells [24], we examined the levels of AR protein expression in our nism in prostate epithelial cells [24], we examined the levels of AR protein expression in docetaxel-resistant cell lines
We examined whether expression of TRAIL was affected by ABCB1 efflux function in our docetaxel-resistant cell lines
Summary
Prostate cancer (PCa) is the most common cancer among men in developed countries and a major cause of male mortality, mostly due to disease progression to metastatic castration-resistant prostate cancer (mCRPC) [1,2]. Responses are invariably limited in time and patients eventually succumb to disease progression because of acquired drug resistance; 3-year progression-free survival rates for docetaxel treatment are below 1% [9]. The mechanisms through which PCa becomes resistant to docetaxel are not completely understood, previous studies have identified multiple mechanisms of resistance. These include, but are not limited to, enhanced intracellular drug extrusion activity mediated by members of the family of adenosine triphosphate-binding cassette (ABC) transporters, such as ABCB1/P-glycoprotein (P-gp) [10], modulation of cell death processes such as apoptosis and autophagy [11,12], mutations in β-tubulin [13], and modified AR signaling [14,15]
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