MAOA-a novel decision maker of apoptosis and autophagy in hormone refractory neuroendocrine prostate cancer cells

Yi-Cheng Lin,Mel Campbell,Chin-Chen Pan,Hsin-Chen Lee,Pei-Ching Chang,Jean C Shih,Tzu-Ping Lin,Yi-Ting Chang

doi:10.1038/srep46338

Abstract

Autophagy and apoptosis are two well-controlled mechanisms regulating cell fate. An understanding of decision-making between these two pathways is in its infancy. Monoamine oxidase A (MAOA) is a mitochondrial enzyme that is well-known in psychiatric research. Emerging reports showed that overexpression MAOA is associated with prostate cancer (PCa). Here, we show that MAOA is involved in mediating neuroendocrine differentiation of PCa cells, a feature associated with hormone-refractory PCa (HRPC), a lethal type of disease. Following recent reports showing that NED of PCa requires down-regulation of repressor element-1 silencing transcription factor (REST) and activation of autophagy; we observe that MAOA is a novel direct target gene of REST. Reactive oxygen species (ROS) produced by overexpressed MAOA plays an essential role in inhibiting apoptosis and activating autophagy in NED PCa cells. MAOA inhibitors significantly reduced NED and autophagy activation of PCa cells. Our results here show MAOA as a new decision-maker for activating autophagy and MAOA inhibitors may be useful as a potential therapy for neuroendocrine tumors.

Highlights

REST, known as neuron restrictive silencing factor (NRSF), was originally identified as a critical transcription repressor that silences neuronal gene expression in neural progenitor and non-neuronal cells
monoamine oxidase A (MAOA) is a novel target of REST and is up-regulated in NE differentiated Prostate cancer (PCa) cells
To study the potential role of MAOA in NE PCa cells, three prostate carcinoma cell lines, LNCaP, PC3 and DU145 that can be induced for neuroendocrine differentiation (NED) were tested[39]

Summary

Introduction

REST, known as neuron restrictive silencing factor (NRSF), was originally identified as a critical transcription repressor that silences neuronal gene expression in neural progenitor and non-neuronal cells. MAOA was originally identified as a mitochondrial outer membrane-bound enzyme that catalyzes oxidative deamination of monoamine neurotransmitters and subsequently generates hydrogen peroxide (H2O2) as a catalytic byproduct[18,19]. Though ROS and many mitochondria outer membrane proteins have been implicated as causal or contributory factors for mitophagy activation, the underlying mechanisms and target proteins, remain largely unknown This is the first study that investigates the expression and regulation of MAOA in human NE PCa cells. We elucidated that MAOA, a mitochondrial outer membrane-bound enzyme that produces H2O2, functions as a key regulator in a cell fate-decision by inhibiting apoptosis and activating autophagy. Our results indicate that targeting MAOA may be a potential useful addition to combination therapy in treating different types of NE tumors

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Conclusion