Targeting MTA1/HIF-1alpha Signaling by Pterostilbene in Combination with Histone Deacetylase Inhibitor Attenuates Prostate Cancer Progression (Open Access)
MISSISSIPPI UNIV JACKSON JACKSON United States
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The metastasis-associated protein 1MTA1histone deacetylase HDAC unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer PCa. In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene Pter, affect MTA1HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA suberoylanilide hydroxamic acid, vorinostat, which also downregulates MTA1, could block prostate tumor progression in vivo. We generated and utilized a luciferase reporter in a prostate-specific Pten-null mouse model Pb-Cre Ptenff Rosa26Luc to evaluate the anticancer efficacy of PterSAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associatedproangiogenic factors HIF-1,VEGF, and IL-1leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition ofMTA1HIF-1than by high dose SAHA alone. Our study provides preclinical evidence that PterSAHA combination treatment inhibits MTA1HIF-1tumor-promoting signaling in PCa. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targetedtherapies in PCa.
- Medicine and Medical Research