title: MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions.
abstract: Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210, USA. Electronic address: boyang.wu@wsu.edu.
authors.forename: Jason Boyang
authors.initials: JB
authors.lastname: Wu
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Yin
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Shi
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Duan
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jen-Ming
authors.initials: JM
authors.lastname: Huang
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Urology, Changhai Hospital, the Secondary Military Medical University, Shanghai 200433, China.
authors.forename: Fubo
authors.initials: F
authors.lastname: Wang
authors.affiliation: West Los Angeles VA Medical Center, Los Angeles, CA 90073, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lewis
authors.affiliation: Department of Pathology, Changhai Hospital, the Secondary Military Medical University, Shanghai 200433, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan 11217, ROC; Department of Urology, School of Medicine and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan 11217, ROC.
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Lin
authors.affiliation: Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan 11217, ROC.
authors.forename: Chin-Chen
authors.initials: CC
authors.lastname: Pan
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Posadas
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.affiliation: Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: Leland.Chung@cshs.org.
authors.forename: Leland W K
authors.initials: LWK
authors.lastname: Chung
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary; D002450:Cell Communication; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008995:Monoamine Oxidase / Q000032:analysis / Q000502:physiology*; D010006:Osteoblasts / Q000502:physiology; D011471:Prostatic Neoplasms / Q000473:pathology*; D053245:RANK Ligand / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: D053823:Hedgehog Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D053245:RANK Ligand; C509239:SHH protein, human; C505688:TNFSF11 protein, human; D008995:Monoamine Oxidase
keywords: bone metastasis; interleukin-6; monoamine oxidase A; osteoblast; osteoclast; prostate cancer; receptor activator of NF-kB ligand; sonic hedgehog signaling; tumor-stromal interactions; visceral metastasis