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

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

doi:10.1038/srep46338

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

Sci Rep. 2017 Apr 12:7:46338. doi: 10.1038/srep46338.

Authors

Yi-Cheng Lin^{1

2

3}, Yi-Ting Chang¹, Mel Campbell⁴, Tzu-Ping Lin^{5

6

7}, Chin-Chen Pan⁸, Hsin-Chen Lee², Jean C Shih^{3

9

10}, Pei-Ching Chang^{1

11}

Affiliations

¹ Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
² Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
³ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
⁴ UC Davis Cancer Center, University of California, Davis, CA 95616, USA.
⁵ Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.
⁶ Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan.
⁷ Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan.
⁸ Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.
⁹ USC-Taiwan Center for Translational Research, University of Southern California, Los Angeles, CA 90089, USA.
¹⁰ Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, 1975 Zonal Ave., Los Angeles, CA 90033, USA.
¹¹ Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgen Antagonists / pharmacology
Androgen Antagonists / therapeutic use
Antineoplastic Agents, Hormonal / pharmacology
Antineoplastic Agents, Hormonal / therapeutic use
Apoptosis* / drug effects
Autophagy* / drug effects
Biomarkers
Carcinoma, Neuroendocrine / drug therapy
Carcinoma, Neuroendocrine / genetics
Carcinoma, Neuroendocrine / metabolism*
Carcinoma, Neuroendocrine / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm*
Enzyme Activation
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Humans
Male
Mitophagy
Models, Biological
Monoamine Oxidase / genetics
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / pharmacology
Monoamine Oxidase Inhibitors / therapeutic use
Neoplasm Grading
Promoter Regions, Genetic
Prostatic Neoplasms / drug therapy
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Prostatic Neoplasms / pathology
Protein Binding
Reactive Oxygen Species / metabolism
Repressor Proteins / metabolism

Substances

Androgen Antagonists
Antineoplastic Agents, Hormonal
Biomarkers
Monoamine Oxidase Inhibitors
RE1-silencing transcription factor
Reactive Oxygen Species
Repressor Proteins
Monoamine Oxidase