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Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis
Jason Boyang Wu, … , Jean C. Shih, Leland W.K. Chung
Jason Boyang Wu, … , Jean C. Shih, Leland W.K. Chung
Published May 27, 2014
Citation Information: J Clin Invest. 2014;124(7):2891-2908. https://doi.org/10.1172/JCI70982.
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Research Article Oncology Article has an altmetric score of 52

Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis

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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

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Figure 9

The HIF1α/VEGF-A/FOXO1/TWIST1 pathway is manifested in high–Gleason grade PCa.

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The HIF1α/VEGF-A/FOXO1/TWIST1 pathway is manifested in high–Gleason grad...
(A) Sixty specimens of human PCa including 30 Gleason grade 3 tumors and 30 Gleason grade 5 tumors were immunostained for MAOA, HIF1α, VEGF-A, FOXO1, pFOXO1, and TWIST1. Original magnification, ×400; scale bars: 20 μm. (B) Semiquantitative analysis of IHC staining was performed for all specimens to assess both the percentage of cells stained and the intensity of each staining. This analysis is reported as the quotient (Q) of these 2 parameters (mean ± SEM). Details are given in Supplemental Methods. Images representative of the mean Q for each IHC staining are shown. **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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