Targeting MTA 1/ HIF ‐1 α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

Autor: Nasir A. Butt, Israh Akhtar, Anait S. Levenson, Swati Dhar, Avinash Kumar, Janice M. Lage, John C. Hancock, Charles R. Pound, Jack R. Lewin, Agnes M. Rimando, Christian R. Gomez
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
pterostilbene
Cancer Research
Pterostilbene
Pten knockout mice
Interleukin-1beta
Vascular Endothelial Growth Factor C
Hydroxamic Acids
Mice
chemistry.chemical_compound
Prostate cancer
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Stilbenes
Original Research
Cancer Biology
Mice
Knockout
Vorinostat
biology
Histone deacetylase inhibitor
SAHA
prostate cancer
Oncology
030220 oncology & carcinogenesis
Signal Transduction
Combination strategy
medicine.drug
Cell Survival
medicine.drug_class
Histone Deacetylases
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
PTEN
Radiology
Nuclear Medicine and imaging
Gene Silencing
Cell Proliferation
PTEN Phosphohydrolase
Prostatic Neoplasms
Cancer
Hypoxia-Inducible Factor 1
alpha Subunit
medicine.disease
Repressor Proteins
030104 developmental biology
chemistry
Tumor progression
MTA1
Immunology
Trans-Activators
biology.protein
Cancer research
Histone deacetylase
Transcription Factors
Zdroj: Cancer Medicine
ISSN: 2045-7634
DOI: 10.1002/cam4.1209
Popis: 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‐1α, VEGF, and IL‐1β 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‐1α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF‐1α 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.
Databáze: OpenAIRE
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