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Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation.

ABSTRACT: Multi-drug resistance (MDR)-ATP binding cassette (ABC) transporters, ABCB1, ABCC1, and ABCG2 participate in the efflux of steroid hormones, estrogens, and androgens, which regulate prostate development and differentiation. The role of MDR-ABC efflux transporters in prostate epithelial proliferation and differentiation remains unclear. We hypothesized that MDR-ABC transporters regulate prostate differentiation and epithelium regeneration. Prostate epithelial differentiation was studied using histology, sphere formation assay, and prostate regeneration induced by cycles of repeated androgen withdrawal and replacement. Embryonic deletion of Abcg2 resulted in a decreased number of luminal cells in the prostate and increased sphere formation efficiency, indicating an imbalance in the prostate epithelial differentiation pattern. Decreased luminal cell number in the Abcg2 null prostate implies reduced differentiation. Enhanced sphere formation efficiency in Abcg2 null prostate cells implies activation of the stem/progenitor cells. Prostate regeneration was associated with profound activation of the stem/progenitor cells, indicating the role of Abcg2 in maintaining stem/progenitor cell pool. Since embryonic deletion of Abcg2 may result in compensation by other ABC transporters, pharmacological inhibition of MDR-ABC efflux was performed. Pharmacological inhibition of MDR-ABC efflux enhanced prostate epithelial differentiation in sphere culture and during prostate regeneration. In conclusion, Abcg2 deletion leads to activation of the stem/progenitor cells and enhances differentiating divisions; and pharmacological inhibition of MDR-ABC efflux leads to epithelial differentiation. Our study demonstrates for the first time that MDR-ABC efflux transporter inhibition results in enhanced prostate epithelial cell differentiation.

SUBMITTER: Samant MD

PROVIDER: S-EPMC4424973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We have recently shown that in vivo inhibition of histone deacetylase (HDAC) stimulates endogenous myocardial regeneration in infarcted hearts (Zhang L et al. J Pharmacol Exp Ther 341: 285-293, 2012). Furthermore, our observation demonstrates that HDAC inhibition promotes cardiogenesis, which is associated with HDAC4 reduction. However, it remains unknown as to whether specific inhibition of HDAC4 modulates cardiac stem cells (CSCs) to facilitate myocardial repair and to preserve cardiac performance. c-kit(+) CSCs were isolated from adult mouse hearts and were transfected with HDAC4 siRNA to knockdown HDAC4 of c-kit(+) CSCs. The transfection of HDAC4 siRNA caused a marked reduction of HDAC4 mRNA and proteins in c-kit(+) CSCs. Mouse myocardial infarction (MI) was created to assess the effect of HDAC4 inhibition in c-kit(+) CSCs on myocardial regeneration in vivo when cells were introduced into MI hearts. Transplantation of HDAC4 siRNA-treated c-kit(+) CSCs into MI hearts improved ventricular function, attenuated ventricular remodeling, and promoted CSC-derived regeneration and neovascularization. Furthermore, Ki67 and BrdU positively proliferative myocytes increased in MI hearts receiving HDAC4 siRNA-treated c-kit(+) CSCs compared with MI hearts engrafted with control siRNA-treated c-kit(+) CSCs. In addition, compared with MI hearts engrafted with control adenoviral GFP-infected c-kit(+) CSCs, MI hearts receiving adenoviral HDAC4-infected c-kit(+) CSCs exhibited attenuated cardiac functional recovery, CSC-derived regeneration, and neovascularization, which was accompanied with adverse ventricular remodeling and decrease in Ki67 and BrdU positively proliferative myocytes. HDAC4 inhibition facilitated c-kit(+) CSCs into the differentiation into cardiac lineage commitments in vitro, while HDAC4 overexpression attenuated c-kit(+) CSC-derived cardiogenesis. Our results indicate that HDAC4 inhibition promotes CSC-derived cardiac regeneration and improves the restoration of cardiac function.

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Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation.

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