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Therapeutic targeting of splicing in aggressive prostate cancer

ABSTRACT: Androgen deprivation therapy (ADT) is the main therapeutic regimen for patients with advanced prostate cancer (PCa). However, most treated patients invariably develop the castration-resistant disease (i.e., CRPC). Mechanisms underlying CRPC development and maintenance remain poorly understood. Recent studies have established splicing dysregulation as a new molecular hallmark of cancer. However, the functional and clinical relevance of such misregulation have not been systematically explored in PCa. Experimentally, we show that splicing modulator, E7107, can significantly inhibits CRPC cell growth both in vitro and in vivo. To determine the mechanistic origins of therapeutic effect of E7107 in vitro, we treated AR+ LNCaP and AR- PC3 cells with DMSO or E7107 at 10nM for 6 h, followed by deep RNA-seq analysis of rRNA-depleted total RNAs isolated from biological triplicates. Furthermore, to evaluate the activity of E7107 against CRPC in vivo, we utilized Enzalutamide-resistant LAPC9-AI (androgen-independent) and PC3 models. RNA-seq experiments we performed on tumors exactly 4 h after the fifth injection of E7107 (5mg/kg/day, 5-days injection considered as 1-dose treatment). Five tumors were included for each group (vehicle or E7107) for deep RNA-seq.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128515 | GEO | 2020/03/04

REPOSITORIES: GEO

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Project description:The development and progression of castrate resistant prostate cancer (CRPC), a lethal disease, is thought to be driven by multiple events. A hallmark of CRPC is the ability to evade the cytotoxic effects of anti-androgen therapy. Importantly, persistent androgen receptor (AR) signalling is thought to play a principal role in maintaining CRPC. The precise molecular alterations driving this condition, however, are not clearly understood. Our previous studies identified specific metabolic alterations associated with localized prostate cancer (PCa) and CRPC, implicating metabolic re-programming in disease progression. Building on these findings, using a novel network-based integromics approach, here we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. We found expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in androgen dependent (AD) PCa while relatively diminished in CRPC possessing either full length AR (AR-FL) or the spliced V7 variant (AR-V7). Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased proliferation and aggressiveness, both, in vitro and in vivo. This was mediated by specific cell cycle genes regulated by the PI3K-AKT pathway activating either AR in cells with AR-FL or SP1-ChREBP (carbohydrate response element binding protein) in cells containing AR-V7. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP) to CRPC-like cells reduced the expression of cell cycle genes and attenuated tumor cell proliferation, both in vitro and in vivo. Furthermore, addition of UDP sensitized CRPC-like cells, inclusive of those possessing AR-V7, to enzalutamide, demonstrating the therapeutic value of targeting altered metabolic pathways in lethal PCa. We anticipate that our findings will motivate the development of novel metabolic therapeutic strategies that complement existing treatments for men with lethal prostate cancer We used microarray analysis to determine key molecular alterations associated with inhibition of HBP pathway in CRPC by knocking down GNPNAT1 transcript level using lentiviral particle bearing shRNA in 22Rv1 and LNCaP-ABL cells GNPNAT1 expression was knockdown in two independent prostate cancer cells, 22Rv1 and LNCaP-ABL

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Therapeutic targeting of splicing in aggressive prostate cancer

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