Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis.

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.

• Authors: Jason Boyang Wu, Chen Shao, Xiangyan Li, Qinlong Li, Peizhen Hu, Changhong Shi, Yang Li, Yi-Ting Chen, Fei Yin, Chun-Peng Liao, Bangyan L Stiles, Haiyen E Zhau, Jean C Shih, Leland W K Chung
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 7 Pg. 2891-908 (Jul 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24865426 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• FOXO1 protein, human
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• TWIST1 protein, human
• Twist-Related Protein 1
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Monoamine Oxidase
• monoamine oxidase A, human

Topics

• Animals
• Carcinogenesis
• Cell Line, Tumor
• Disease Progression
• Epithelial-Mesenchymal Transition
• Forkhead Box Protein O1
• Forkhead Transcription Factors (metabolism)
• Gene Knockdown Techniques
• Heterografts
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Mice, SCID
• Models, Biological
• Monoamine Oxidase (genetics, metabolism)
• Neoplasm Metastasis
• Nuclear Proteins (genetics)
• Promoter Regions, Genetic
• Prostatic Neoplasms (enzymology, etiology, pathology)
• Signal Transduction
• Twist-Related Protein 1 (genetics)
• Up-Regulation
• Vascular Endothelial Growth Factor A (genetics, metabolism)