Association of Monoamine Oxidase A with Tumor Burden and Castration Resistance in Prostate Cancer

Abstract

Background Metastatic burden and aggressive behavior determine severity stratification and guide treatment decisions in prostate cancer (PCa). Monoamine oxidase A (MAOA) may promote tumor burden and drug/castration resistance in PCa. A positive association will pave the way for MAOA inhibitors such as moclobemide for PCa therapy. Objective To analyze MAOA in peripheral blood mononuclear cells qualitatively and p38, c-Jun N-terminal kinases, nuclear factor kappa B, and their phosphorylated forms, vascular endothelial growth factor (angiogenesis), transforming growth factor beta, interleukin 6, and tumor necrosis factor-α (cytokines), Bcl-2 associated X, B-cell lymphoma 2, and P53 (apoptosis), prostate-specific membrane antigen, and epithelial cell adhesion molecules (surface markers) in plasma of patients with PCa. Methods This was a 1-year pilot study in which patients with PCa were recruited and stratified into 2 groups and subgroups: treatment-naive with (M1) (n = 23) or without (M0) (n = 23) bone metastasis; hormone-sensitive prostate cancer (n = 26) or hormone/castration-resistant prostate cancer (n = 26). MAOA was detected using ELISA and other proteins were detected using immunoblotting technique. Results MAOA was detected in 8.6% of M0 compared with 30.4% of M1 patients, and in 7.7% of hormone-sensitive compared with 27% of hormone/castration resistant PCa patients, associating it with bone metastasis and castration resistance. Multivariable regression analysis showed a correlation of MAOA with serum prostate-specific antigen, a marker for progression in PCa (Pearson correlation coefficient r = 0.30; P < 0.01). In patients with positive MAOA, there was overexpression of p38, phosphorylated-p38, c-Jun N-terminal kinases, phosphorylated c-Jun N-terminal kinases, nuclear factor kappa B, phosphorylated nuclear factor kappa B, transforming growth factor beta, vascular endothelial growth factor, interleukin 6, tumor necrosis factor α, Bcl-2 associated X, B-cell lymphoma 2, prostate-specific membrane antigen, and epithelial cell adhesion molecule in M1 compared with M0 group patients, associating these proteins with tumor burden. Overexpression of Bcl-2 associated X, tumor protein 53, c-Jun N-terminal kinases, nuclear factor kappa B, transforming growth factor beta, vascular endothelial growth factor, and prostate-specific membrane antigen and underexpression of B-cell lymphoma 2 and phosphorylated nuclear factor kappa B were observed in hormone-sensitive prostate cancer compared with hormone/castration-resistant prostate cancer, associating these proteins with castration resistance. Conclusions Association of key molecules of oncogenesis and metastasis with MAOA suggests that MAOA inhibitors such as moclobemide might be effective in the management of PCa.

Targeting monoamine oxidase A: a strategy for inhibiting tumor growth with both immune checkpoint inhibitors and immune modulators

“…MAOA is highly expressed in PCa [ 87 ], and its degree of expression varies with disease development [ 88 ]. Previous results demonstrated that MAOA was associated with PCa progression and played key roles during almost every stage of PCa development, including castrate-resistant PCa, neuroendocrine PCa, metastasis, drug resistance, stemness, and perineural invasion.…”

Monoamine oxidase A: An emerging therapeutic target in prostate cancer

“…MAOA induces YAP1 through downstream ROS/Twist1-dependent activation of Shh/Gli signaling for direct Gli1/2 interaction with a Gli-binding site in YAP1 promoter ( 31 ). Of note, MAOA expression is elevated and associated with AR activity in CRPC clinical specimens ( 31 , 32 ). Importantly, knocking down MAOA expression impeded tumor growth of both androgen-dependent LNCaP cells and castration-resistant C4-2B ENZR cells (a LNCaP-derived CRPC subline with acquired resistance to the antiandrogen drug enzalutamide) ( 31 ), indicating that MAOA is a valid target for AR-positive PC cells regardless of cellular reliance on androgens.…”

Revisiting monoamine oxidase inhibitors: A potential dual-action therapy for patients with prostate cancer and comorbid depression?

“…There are several explanations for the antiproliferative effects of MAO inhibitors in prostate cancer patients. A relationship between higher MAO levels and prostate-specific antigen (PSA), as well as the degree of severity of tumor progression, has been empirically demonstrated (Meenu et al, 2020). One important finding is based on the effect of MAO-A on epithelial-to-mesenchymal transition mediated signaling pathways.…”