Targeting MTA1/HIF-1 signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

被引:41
作者
Butt, Nasir A. [1 ,2 ]
Kumar, Avinash [1 ,3 ]
Dhar, Swati [1 ,4 ]
Rimando, Agnes M. [5 ]
Akhtar, Israh [2 ]
Hancock, John C. [2 ]
Lage, Janice M. [2 ]
Pound, Charles R. [6 ]
Lewin, Jack R. [2 ]
Gomez, Christian R. [1 ,2 ,4 ]
Levenson, Anait S. [1 ,2 ,3 ]
机构
[1] Univ Mississippi, Med Ctr, Inst Canc, Jackson, MS 39216 USA
[2] Univ Mississippi, Med Ctr, Dept Pathol, Jackson, MS 39216 USA
[3] Long Isl Univ, Arnold & Marie Schwartz Coll Pharm & Hlth Sci, Brooklyn, NY 11201 USA
[4] Univ Mississippi, Med Ctr, Dept Radiat Oncol, Jackson, MS 39216 USA
[5] ARS, USDA, Nat Prod Utilizat Res Unit, University, MS USA
[6] Univ Mississippi, Med Ctr, Dept Surg, Div Urol, Jackson, MS 39216 USA
来源
CANCER MEDICINE | 2017年 / 6卷 / 11期
关键词
Combination strategy; MTA1; prostate cancer; Pten knockout mice; pterostilbene; SAHA; SUBEROYLANILIDE HYDROXAMIC ACID; TRANSCRIPTIONAL REPRESSION; MTA FAMILY; RESVERATROL; EXPRESSION; VORINOSTAT; PATHWAY; CELLS; GENE; CHEMOSENSITIZATION;
D O I
10.1002/cam4.1209
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The metastasis-associated protein 1(MTA1)/histone 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 MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC 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(+); Pten(f/f); Rosa26(Luc/+)) to evaluate the anticancer efficacy of Pter/SAHA 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-associated proangiogenic factors HIF-1, VEGF, and IL-1 leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/HIF-1 than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF-1 tumor-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-targeted therapies in PCa.
引用
收藏
页码:2673 / 2685
页数:13
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