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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 4

MAOA promotes VEGF-A/NRP1–mediated activation of AKT/FOXO1 signaling.

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MAOA promotes VEGF-A/NRP1–mediated activation of AKT/FOXO1 signaling.
(A...
(A) qPCR analysis of VEGFA mRNA expression (mean ± SEM, n = 3) in paired PC-3 and LNCaP cells as indicated (left). VEGF-A secretion (mean ± SEM, n = 3) in culture media from these cells was quantified by ELISA (right). *P < 0.05, **P < 0.01. (B) Immunoblots of PC-3 (vector and MAOA-overexpression) cells for NRP1. (C) IHC analysis of PC-3 (vector and MAOA-overexpression) tumor xenografts for VEGF-A and NRP1 expression. Representative images from 5 separate samples are shown. Original magnification, ×400; scale bars: 20 μm. (D) Immunoblots of paired PC-3 and LNCaP cells as indicated for pAKT (Ser473), pFOXO1 (Thr24), total AKT, and FOXO1. (E) Immunoblots of PC-3 (vector and MAOA-overexpression) cells that express NRP1-targeting shRNAs (shNRP1) or a scrambled shRNA (shCon) for NRP1, pAKT (Ser473), and pFOXO1 (Thr24). (F) Immunoblots of nuclear and cytoplasmic extracts from different groups of paired PC-3 cells as indicated for FOXO1. Lamin B1 and GAPDH serve as nuclear and cytoplasmic protein markers, respectively. (G) Immunoblots of PC-3 (vector and MAOA-overexpression) cells treated with either anti–VEGF-A antibody or a control IgG (0.5 μg/ml, 24 hours) for pAKT (Ser473) and pFOXO1 (Thr24). (H) PC-3 cells as established in E were assessed for their ability to either migrate (left) or invade (right). Data represent the mean ± SEM (n = 3). *P < 0.05, **P < 0.01. (I) Growth curves of PC-3 cells as established in E. Data represent the mean ± SEM (n = 3). **P < 0.01.

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

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