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Differential gene expression induced by anti-cancer agent plumbagin is mediated by androgen receptor in prostate
Gaelle Rondeau1, Parisa Abedinpour1, Adrian Chrastina1
1Vaccine Research Institute of San Diego, 3030 Bunker Hill Street, Suite 200, San Diego, CA, 92109, USA.
Abstract:
Treatment of mice harboring PTEN-P2 tumors in the prostate or on prostate tissue in vivo with 5-hydroxy-2-methyl-1,4-naphthoquinone, also known as plumbagin, results in tumor regression in castrated mice, but not in intact mice. This suggested that dihydrotestosterone (DHT) production in the testes may prevent cell death due to plumbagin treatment, but the underlying mechanism is not understood. We performed RNA-seq analysis on cells treated with combinations of plumbagin and DHT, and analyzed differential gene expression, to gain insight into the interactions between androgen and plumbgin. DHT and plumbagin synergize to alter the expression of many genes that are not differentially regulated by either single agent when used alone. These experiments revealed that, for many genes, increases in mRNAs caused by DHT are sharply down-regulated by plumbagin, and that many transcripts change in response to plumbagin in a DHT-dependent manner. This suggests that androgen receptor mediates some of the effects of plumbagin on gene expression.
Insights
Plumbagin, a prostate cancer drug, effectively regresses tumors in castrated mice. Dihydrotestosterone (DHT) in intact mice counteracts plumbagin by altering gene expression via the androgen receptor.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer progression is linked to androgens like dihydrotestosterone (DHT).
- Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) shows tumor-regressing effects in prostate cancer models.
- DHT appears to interfere with plumbagin's efficacy in intact mice, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying DHT's interference with plumbagin treatment in prostate cancer.
- To investigate the interaction between androgen signaling and plumbagin at the gene expression level.
Main Methods:
- RNA sequencing (RNA-seq) was performed on cells treated with plumbagin and DHT, alone and in combination.
- Differential gene expression analysis was conducted to identify genes regulated by these treatments.
Main Results:
- DHT and plumbagin synergistically alter the expression of numerous genes not affected by single agents.
- Plumbagin significantly down-regulates DHT-induced mRNA increases in many genes.
- Plumbagin's effects on many transcripts are dependent on the presence of DHT.
Conclusions:
- Androgen receptor signaling mediates some of plumbagin's effects on gene expression in prostate cancer cells.
- DHT antagonizes plumbagin's anti-cancer activity by modulating gene expression, likely through the androgen receptor.
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