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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 HIF1?, 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 HIF1?/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.

SUBMITTER: Wu JB

PROVIDER: S-EPMC4071401 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis.

Wu Jason Boyang JB Shao Chen C Li Xiangyan X Li Qinlong Q Hu Peizhen P Shi Changhong C Li Yang Y Chen Yi-Ting YT Yin Fei F Liao Chun-Peng CP Stiles Bangyan L BL Zhau Haiyen E HE Shih Jean C JC Chung Leland W K LW

The Journal of clinical investigation 20140527 7

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 o ...[more]

PMID: 24865426

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Project description:BackgroundMonoamine oxidase A (MAOA) is a mitochondrial enzyme that is involved in prostate tumorigenesis and cancer metastasis. The predictive power of the preoperative clinical and pathological indicators for prostate cancer(PC) remains to be improved. To enrich evidence regarding the value of MAOA as a prognostic biomarker in clinical practice, this study explored the significance of MAOA expression as a prognostic marker for patients with PC after radical prostatectomy-pelvic lymph node dissection (RP-PLND).MethodsMAOA expression was analyzed in 50 benign prostate tissues and 115 low-intermediate risk and 163 high-risk PC tissues using tissue immunohistochemistry (IHC). Propensity score matching, survival analysis and COX regression analysis were conducted to investigate the correlation between high MAOA expression and progression free survival (PFS) in PC patients.ResultsMAOA expression was increased in PC patients, especially in those with high risk PC and pathological lymph node (pLN) metastasis. High MAOA expression was significantly associated with PSA recurrence for both low-intermediate risk PC patients (log-rank test: P = 0.02) and high risk PC patients (log-rank test: P = 0.03). Cox regression analysis revealed that high MAOA expression was an adverse prognostic factor for both low-intermediate risk PC patients (hazard ratio [HR] 2.74, 95% confidence interval [CI] 1.26-5.92; P = 0.011) and high risk PC patients (HR 1.73, 95% CI 1.11-2.71; P = 0.016). High MAOA expression was also significantly associated with PSA recurrence in high risk PC patients developed into castration-resistant prostate cancer (CRPC) and were receiving abiraterone therapy (log-rank: P = 0.01).ConclusionsMAOA expression correlates with the malignant progression of PC. High MAOA expression may be a poor prognostic marker for patients with PC after RP-PLND. More careful follow up or potential of adjuvant hormonal therapy may be addressed for patients with high MAOA expression.

Project description:PurposeMonoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer.Materials and methodsAn open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by PSA ≥ 0.4 ng/ml (post prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline.ResultsCharacteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥30% and ≥50% were observed in 25% (n = 5/20) and 10% (n = 2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥30% and ≥50% of 24% (n = 4/17) and 6% (n = 1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2 = 35%), hypertension (grade ≥ 2 = 30%), and edema (grade 1 = 25%, grade 2 = 10%). There was one episode of grade 4 hypertension (cycle 4) and two episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment.ConclusionsPhenelzine demonstrated efficacy in patients with biochemical recurrent castrate-sensitive prostate cancer. Most treatment-related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer.

Project description:BackgroundHigh expression of monoamine oxidase A (MAOA) in non-small cell lung cancer (NSCLC) is related to epithelial-mesenchymal transition (EMT) and the development of clinicopathological features of NSCLC. Nevertheless, the role of MAOA in drug resistance still remains unclear. Hence, the aim of this article was to evaluate a previously synthesized MAOA inhibitor (G11) on inhibiting paclitaxel-resistant NSCLC metastasis and growth.MethodsFirst, MAOA expression level was evaluated in several NSCLC cell lines. An MTT assay was used to validate the inhibitory effect of G11 on NSCLC cells in vitro. Second, gene expression in G11-treated H460/PTX cells was analyzed by microarray gene expression. Third, transwell assay was performed to assess the invasion and metastasis of G11-treated A549/PTX and H460/PTX cells and western blot assay used to analyze vital protein expression level in G11-treated H460/PTX cells. Finally, the antimetastatic effect of G11 was tested in an NSCLC in vivo model.ResultsOur data revealed that G11 significantly inhibited the viability of paclitaxel (PTX)-resistant NSCLC cell lines (A549/PTX and H460/PTX). G11 dramatically reduced the expression of MAOA in A549/PTX and H460/PTX cells, which exhibited relatively high MAOA expression levels. Additionally, G11 was found to hinder A549/PTX and H460/PTX cell migration and invasion. Furthermore, the in vivo study indicated that the coadministration of G11 and paclitaxel significantly suppressed tumor metastasis in H460/PTX lung metastasis models.ConclusionsThese findings indicated G11 showed a moderate inhibitory effect on paclitaxel-resistant NSCLC metastasis and growth, and support further investigation on MAOA potentially as a promising therapeutic target for paclitaxel-resistant NSCLC treatment.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: Inhibition of MAOA might contribute to the suppression of metastasis and growth in PTX-resistant NSCLC cells. What this study adds This study explored the potential function of MAOA in drug-resistant NSCLC and might consider MAOA as a promising target for the treatment of drug-resistant NSCLC.

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Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis.

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Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis.

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