title: The monoamine oxidase-A inhibitor clorgyline promotes a mesenchymal-to-epithelial transition in the MDA-MB-231 breast cancer cell line.
abstract: Monoamine oxidase-A (MAO-A) dysfunction has been historically associated with depression. Recently, depression as well as altered MAO-A expression have both been associated with a poor prognosis in cancers, although the mechanism involved remains ambiguous. For example, MAO-A mRNA is repressed across cancers, yet MAO-A protein and levels of serotonin, a substrate of MAO-A implicated in depression, are paradoxically increased in malignancies, including breast cancer. The effect of clorgyline (CLG), a selective inhibitor of MAO-A, on malignant behaviour, expression of transitional markers, and biochemical correlates was examined in two human breast carcinoma cell lines, i.e. the epithelial, oestrogen receptor (ER)-positive MCF-7 cell line and the post-EMT (mesenchymal), ER-negative MDA-MB-231 cell line. CLG exerted little effect on malignant behaviour in MCF-7 cells, but inhibited proliferation and anchorage-independent growth, and increased invasiveness and active migration of MDA-MB-231 cells. CLG induced the expression of the mesenchymal marker vimentin in MCF-7 cells, but not in MDA-MB-231 cells. In contrast, CLG induced the epithelial protein marker E-cadherin in both cell lines, with a more robust effect in MDA-MB-231 cells (where a nuclear E-cadherin signal was also detected). This effect appears to be independent of any canonical Snai1-mediated regulation of E-cadherin mRNA expression. CLG interfered with the β-catenin/[phospho]GSK-3β complex as well as the E-cadherin/β-catenin complex in both cell lines cells, but, again, the effect was more robust in MDA-MB-231 cells. Parallel studies revealed a general lack of effect of CLG on the ER-negative, epithelial Au565 breast cancer cell line. Thus, any effect of CLG on metastatic behaviours appears to rely on the cell's EMT status rather than on the cell's ER status. These data suggest that inactivation of MAO-A triggers a mesenchymal-to-epithelial transition in MDA-MB-231 cells via a non-canonical mechanism. This potentially implicates an MAO-A-sensitive step in advanced breast cancer and should be borne in mind when considering pharmacological treatment options for co-morbid depression in breast cancer patients.
authors.affiliation: Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Canada. Electronic address: tsatram@gmail.com.
authors.forename: Tamara
authors.initials: T
authors.lastname: Satram-Maharaj
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Canada. Electronic address: jnn270@mail.usask.ca.
authors.forename: Jennifer N K
authors.initials: JN
authors.lastname: Nyarko
authors.affiliation: Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Canada. Electronic address: kellykuski@gmail.com.
authors.forename: Kelly
authors.initials: K
authors.lastname: Kuski
authors.affiliation: Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Canada. Electronic address: kdf044@mail.usask.ca.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Fehr
authors.affiliation: Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Canada. Electronic address: prp676@mail.usask.ca.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Pennington
authors.affiliation: Department of Pathology, University of Saskatchewan, Canada. Electronic address: luke.truitt@usask.ca.
authors.forename: Luke
authors.initials: L
authors.lastname: Truitt
authors.affiliation: Department of Pathology, University of Saskatchewan, Canada. Electronic address: andrew.freywald@usask.ca.
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Canada. Electronic address: kel232@mail.usask.ca.
authors.forename: Kiven Erique
authors.initials: KE
authors.lastname: Lukong
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Canada. Electronic address: deborah.anderson@saskcancer.ca.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Anderson
authors.affiliation: Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Canada. Electronic address: darrell.mousseau@usask.ca.
authors.forename: Darrell D
authors.initials: DD
authors.lastname: Mousseau
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003010:Clorgyline / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D061986:MCF-7 Cells; D008995:Monoamine Oxidase / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014746:Vimentin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D012333:RNA, Messenger; D014746:Vimentin; D051176:beta Catenin; D008995:Monoamine Oxidase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D003010:Clorgyline
keywords: Breast cancer; Depression; E-cadherin; Mesenchymal-to-epithelial transition; Metastasis; Monoamine oxidase