Journal article
MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness
Oncogene, Vol.39(16), pp.3305-3321
04/2020
PMID: 32066880
Abstract
The tumor microenvironment plays a critical role in prostate cancer (PC) development and progression. Inappropriate activation of the stroma potentiates the growth and transformation of epithelial tumor cells. Here, we show that upregulation of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, in stromal cells elevates production of reactive oxygen species, triggers an inflammatory response including activation of IL-6, and promotes tumorigenesis in vitro and in vivo. Mechanistically, MAOA enhances IL-6 transcription through direct Twist1 binding to a conserved E-box element at the IL-6 promoter. MAOA in stromal fibroblasts provides tumor cell growth advantages through paracrine IL-6/STAT3 signaling. Tissue microarray analysis revealed co-expression correlations between individual pairs of proteins of the stromal MAOA-induced Twist1/IL-6/STAT3 pathway in clinical specimens. Downstream of stromal MAOA, STAT3 also promotes cell stemness and transcriptionally activates expression of cancer stem cell marker CD44 in PC cells. MAOA inhibitor treatment effectively suppressed prostate tumor growth in mice in a stroma-specific targeted manner. Collectively, these findings characterize the contribution of MAOA to stromal activation in PC pathogenesis and provide a rationale for targeting MAOA in stromal cells to treat PC.
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Details
- Title
- MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness
- Creators
- Jingjing Li - Washington State University SpokaneTianjie Pu - Washington State University, Pharmaceutical Sciences, Department ofLijuan Yin - Sichuan UniversityQinlong Li - Xijing HospitalChun-Peng Liao - Lawrence J. Ellison Institute for Transformative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USABoyang Jason Wu - Washington State University, Pharmaceutical Sciences, Department of
- Publication Details
- Oncogene, Vol.39(16), pp.3305-3321
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Grant note
- R37CA233658 / U.S. Department of Health & Human Services | National Institutes of Health (NIH)
- Identifiers
- 99900620490301842
- Language
- English
- Resource Type
- Journal article