title: Chemotherapy-induced monoamine oxidase expression in prostate carcinoma functions as a cytoprotective resistance enzyme and associates with clinical outcomes.
abstract: To identify molecular alterations in prostate cancers associating with relapse following neoadjuvant chemotherapy and radical prostatectomy patients with high-risk localized prostate cancer were enrolled into a phase I-II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pre-treatment prostate tissue was acquired by needle biopsy and post-treatment tissue was acquired by prostatectomy. Prostate cancer gene expression measurements were determined in 31 patients who completed 4 cycles of neoadjuvant chemotherapy. We identified 141 genes with significant transcript level alterations following chemotherapy that associated with subsequent biochemical relapse. This group included the transcript encoding monoamine oxidase A (MAOA). In vitro, cytotoxic chemotherapy induced the expression of MAOA and elevated MAOA levels enhanced cell survival following docetaxel exposure. MAOA activity increased the levels of reactive oxygen species and increased the expression and nuclear translocation of HIF1α. The suppression of MAOA activity using the irreversible inhibitor clorgyline augmented the apoptotic responses induced by docetaxel. In summary, we determined that the expression of MAOA is induced by exposure to cytotoxic chemotherapy, increases HIF1α, and contributes to docetaxel resistance. As MAOA inhibitors have been approved for human use, regimens combining MAOA inhibitors with docetaxel may improve clinical outcomes.
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Gordon
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Mengchu
authors.initials: M
authors.lastname: Wu
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Chung-Ying
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: William P
authors.initials: WP
authors.lastname: Harris
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Hong Gee
authors.initials: HG
authors.lastname: Sim
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Lucas
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Roman
authors.initials: R
authors.lastname: Gulati
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Vessella
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lange
authors.affiliation: Department of Urology and Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, United States of America; Section of Urology, Portland VA Medical Center, Portland, Oregon, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Garzotto
authors.affiliation: Department of Medicine, Oregon Health and Sciences University, Portland, Oregon, United States of America.
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004351:Drug Resistance / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D008995:Monoamine Oxidase / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D043823:Taxoids; D000077143:Docetaxel; D008942:Mitoxantrone; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human