title: Repression of breast cancer cell growth by proteasome inhibitors in vitro: impact of mitogen-activated protein kinase phosphatase 1.
abstract: Mitogen activated protein kinase phosphatase-1 (MKP-1) has emerged as an important protein mediating breast cancer oncogenesis and chemoresistance to cancer chemotherapies, especially proteasome inhibitors. In this in vitro study, we utilized the breast cancer epithelial cell lines MCF-7 and MDA-MB-231, in comparison to MCF-10A control cells, to examine the impact of MKP-1 on breast cancer cell growth and repression by proteasome inhibitors. We confirm that proteasome inhibitors MG-132 and bortezomib induce MKP-1 protein upregulation and we show that one of the ways in which bortezomib increases MKP-1 in breast cancer cells, in addition to inhibition of ubiquitin-proteasome system, is via upregulation of MKP-1 mRNA expression in p38 MAPK-mediated manner. Notably, these effects are specific to cancer cells, as bortezomib activated p38 MAPK and induced MKP-1 in MCF-7 and MDA-MB-231 breast cancer cells, but not in control cells (MCF-10A). We took a dual approach toward targeting MKP-1 to show that bortezomib-induced effects are enhanced. Firstly, treatment with the non-specific MKP-1 inhibitor triptolide reduces breast cancer cell growth and augments proteasome inhibitor-induced effects. Secondly, specific knock-down of MKP-1 with siRNA significantly repressed cell viability by reduced cyclin D1 expression, and enhanced repression of cancer cell growth by proteasome inhibitors. Taken together, these results indicate that removing the unwanted (MKP-1-inducing) effects of bortezomib significantly improves the efficacy of proteasome inhibition in breast cancer cells. Thus, future development of drugs targeting MKP-1 offer promise of combination therapies with reduced toxicity and enhanced cell death in breast cancer.
authors.affiliation: a Faculty of Pharmacy; University of Sydney ; Sydney , NSW , Australia.
authors.forename: Brijeshkumar S
authors.initials: BS
authors.lastname: Patel
authors.forename: Wai Sie
authors.initials: WS
authors.lastname: Co
authors.forename: Claudia
authors.initials: C
authors.lastname: Donat
authors.forename: Mary
authors.initials: M
authors.lastname: Wang
authors.forename: Wenchi
authors.initials: W
authors.lastname: Che
authors.forename: Pavan
authors.initials: P
authors.lastname: Prabhala
authors.forename: Friederike
authors.initials: F
authors.lastname: Schuster
authors.forename: Vera
authors.initials: V
authors.lastname: Schulz
authors.forename: Janet L
authors.initials: JL
authors.lastname: Martin
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D019950:Mitogen-Activated Protein Kinase 1; D010749:Phosphoprotein Phosphatases
keywords: ERK, extracellular signal-regulated kinase; MAPK, mitogen activated protein kinase; MG-132; MKP-1; MKP-1, mitogen activated protein kinase phosphatase-1; TTP, tristetraprolin; bortezomib; breast cancer; cell viability; p38 MAPK