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.
Highlights
Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a small molecule derived from the Plumbaginaceae family, including Plumbago indica and Plumbago zelanica[1,2], certain carnivorous plants of the Droseraceae family[3], plants of the Ebenaceae family[4], wherein it is thought to protect against predation[3], and in species of the Juglans genus[5]
In intravital microscopy (IVM) experiments, PTEN-P2 tumors stop growing upon androgen deprivation therapy (ADT) but do not regress, grow at a slower rate when treated with plumbagin alone, and regress when treated with plumbagin and ADT in combination[6]
In animals with prostate tumors, plumbagin treatment alone and ADT alone failed, but the combination therapy resulted in complete tumor regression[22]
Summary
Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a small molecule derived from the Plumbaginaceae family, including Plumbago indica and Plumbago zelanica[1,2], certain carnivorous plants of the Droseraceae family[3], plants of the Ebenaceae family[4], wherein it is thought to protect against predation[3], and in species of the Juglans genus[5] It has been used in traditional medicine for various purposes, and has been studied more recently as a potential cancer therapeutic[5,6,7,8,9,10,11,12,13]. We used PTEN-P2 cells implanted in the prostate and cultured in vivo in dorsal skin fold chambers as a model of pre-invasive prostate cancer
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