Journal article
Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis
The Journal of clinical investigation, Vol.124(7), pp.2891-2908
07/01/2014
PMCID: PMC4071401
PMID: 24865426
Abstract
Tumors from patients with high-grade aggressive prostate cancer (PCa) exhibit increased expression of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines. Despite the association between MAOA and aggressive PCa, it is unclear how MAOA promotes PCa progression. Here, we found that MAOA functions to induce epithelial-to-mesenchymal transition (EMT) and stabilize the transcription factor HIF1α, which mediates hypoxia through an elevation of ROS, thus enhancing growth, invasiveness, and metastasis of PCa cells. Knockdown and overexpression of MAOA in human PCa cell lines indicated that MAOA induces EMT through activation of VEGF and its coreceptor neuropilin-1. MAOA-dependent activation of neuropilin-1 promoted AKT/FOXO1/TWIST1 signaling, allowing FOXO1 binding at the
TWIST1
promoter. Importantly, the MAOA-dependent HIF1α/VEGF-A/FOXO1/TWIST1 pathway was activated in high-grade PCa specimens, and knockdown of MAOA reduced or even eliminated prostate tumor growth and metastasis in PCa xenograft mouse models. Pharmacological inhibition of MAOA activity also reduced PCa xenograft growth in mice. Moreover, high MAOA expression in PCa tissues correlated with worse clinical outcomes in PCa patients. These findings collectively characterize the contribution of MAOA in PCa pathogenesis and suggest that MAOA has potential as a therapeutic target in PCa.
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Details
- Title
- Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis
- Creators
- Jason Boyang Wu - Washington State University, Pharmaceutical Sciences, Department ofChen Shao - Fourth Military Medical UniversityXiangyan Li - Cedars-Sinai Medical CenterQinlong Li - Xijing HospitalPeizhen Hu - Cedars-Sinai Medical CenterChanghong Shi - Cedars-Sinai Medical CenterYang Li - Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USAYi-Ting Chen - Cedars-Sinai Medical CenterFei Yin - Cedars-Sinai Medical CenterChun-Peng Liao - Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USABangyan L Stiles - Cedars-Sinai Medical CenterHaiyen E Zhau - Cedars-Sinai Medical CenterJean C Shih - University of Southern CaliforniaLeland W.K Chung - Cedars-Sinai Medical Center
- Publication Details
- The Journal of clinical investigation, Vol.124(7), pp.2891-2908
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Publisher
- American Society for Clinical Investigation
- Identifiers
- 99900620489001842
- Language
- English
- Resource Type
- Journal article