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Differential Effect of Non-Steroidal Anti-Inflammatory Drugs Aspirin and Naproxen against TMPRSS2-ERG (Fusion)-Driven and Non-Fusion-Driven Prostate Cancer.

ABSTRACT: The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case-control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both TMPRSS2-ERG (fusion)-driven (with conditional deletion of Pten) and non-TMPRSS2-ERG-driven (Hi-Myc^+/- mice) PCa. Male mice (n = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc^+/- mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the TMPRSS2-ERG (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79-91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc^+/- mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.

SUBMITTER: Raina K

PROVIDER: S-EPMC10605633 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Differential Effect of Non-Steroidal Anti-Inflammatory Drugs Aspirin and Naproxen against <i>TMPRSS2-ERG</i> (Fusion)-Driven and Non-Fusion-Driven Prostate Cancer.

Raina Komal K Kandhari Kushal K Kant Rama R Prasad Ram Raj RR Mishra Neha N Maurya Akhilendra K AK Fox Jennifer T JT Sei Shizuko S Shoemaker Robert H RH Bosland Maarten C MC Maroni Paul P Agarwal Chapla C Agarwal Rajesh R

Cancers 20231019 20

The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing <i>TMPRSS2-ERG</i> (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case-control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, napr ...[more]

PMID: 37894421

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Project description:BackgroundAspirin use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival.MethodsThis prospective analysis includes women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline (1992 or 1993) and diagnosed with CRC during incidence follow-up through 2015. Detailed information on aspirin and non-aspirin NSAID use was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 2686 and 1931 participants without distant metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between prediagnosis aspirin use and stage at diagnosis (distant metastatic vs localized or regional). All statistical tests were 2-sided.ResultsLong-term regular use of aspirin (>15 times per month) before diagnosis was associated with lower CRC-specific mortality (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.52 to 0.92). Postdiagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82, 95% CI = 0.62 to 1.09), although participants who began regular aspirin use only after their diagnosis were at lower risk than participants who did not use aspirin at both the pre- and postdiagnosis periods (HR = 0.60, 95% CI = 0.36 to 0.98). Long-term aspirin use before diagnosis was also associated with lower odds of diagnosis with distant metastases (multivariable-adjusted odds ratio = 0.73, 95% CI = 0.53 to 0.99).ConclusionsOur results suggest that long-term aspirin use before a diagnosis of nonmetastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micrometastases before diagnosis.

Project description:The transmembrane protease serine 2:v‑ets erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion is common in prostate cancer, while its functional role is not fully understood. The present study aimed to investigate the significance of the TMPRSS2:ERG gene fusion in human prostate cancers using bioinformatics tools. Comprehensive alteration analysis of TMPRSS2 and ERG in 148 different human cancer studies was performed by cBioPortal, and the mRNA expression level of the ERG gene was evaluated using Oncomine analysis. Furthermore, lentiviral short hairpin (sh)RNA‑mediated knockdown of TMPRSS2:ERG was performed to study the impact of ERG silencing on cell proliferation and cell cycle distribution in prostate cancer cells. The results demonstrated that the TMPRSS2 and ERG genes were mostly altered in prostate cancer, and the most frequent alteration was gene fusion. Oncomine analysis demonstrated that the ERG gene was significantly upregulated in prostate clinical samples compared with the normal prostate gland in four independent datasets, and a positive association was observed between potassium inwardly‑rectifying channel subfamily J member 15, down syndrome critical region gene 4, potassium inwardly‑rectifying channel subfamily J member 6 and ERG gene expression. There were 272 mutations of the ERG gene identified in the cBioPortal database; among the mutations, 2 missense mutations (R367C and P401H) were regarded as functional mutations (functional impact score >1.938). Furthermore, the present study successfully knocked down ERG gene expression through a lentiviral‑mediated gene silencing approach in VCaP prostate cancer cells. The ERG mRNA and protein expression levels were both suppressed significantly, and a cell‑cycle arrest at G0/G1 phase was observed after ERG gene silencing. In conclusion, these bioinformatics analyses provide novel insights for TMPRSS2:ERG fusion gene study in prostate cancer. Target inhibition of ERG expression could significantly cause cell growth arrest in prostate cancer cells, which could be a potentially valuable target for prostate cancer treatment. However, the precise mechanism of these results remains unclear; therefore, further studies are required.

Dataset Information

Differential Effect of Non-Steroidal Anti-Inflammatory Drugs Aspirin and Naproxen against TMPRSS2-ERG (Fusion)-Driven and Non-Fusion-Driven Prostate Cancer.

Publications

Differential Effect of Non-Steroidal Anti-Inflammatory Drugs Aspirin and Naproxen against <i>TMPRSS2-ERG</i> (Fusion)-Driven and Non-Fusion-Driven Prostate Cancer.

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