title: Chronic Inhibition of STAT3/STAT5 in Treatment-Resistant Human Breast Cancer Cell Subtypes: Convergence on the ROS/SUMO Pathway and Its Effects on xCT Expression and System xc- Activity.
abstract: Pharmacologically targeting activated STAT3 and/or STAT5 has been an active area of cancer research. The cystine/glutamate antiporter, system xc-, contributes to redox balance and export of intracellularly produced glutamate in response to up-regulated glutaminolysis in cancer cells. We have previously shown that blocking STAT3/5 using the small molecule inhibitor, SH-4-54, which targets the SH2 domains of both proteins, increases xCT expression, thereby increasing system xc- activity in human breast cancer cells. The current investigation demonstrates that chronic SH-4-54 administration, followed by clonal selection of treatment-resistant MDA-MB-231 and T47D breast cancer cells, elicits distinct subtype-dependent effects. xCT mRNA and protein levels, glutamate release, and cystine uptake are decreased relative to untreated passage-matched controls in triple-negative MDA-MB-231 cells, with the inverse occurring in estrogen-responsive T47D cells. This "ying-yang" effect is linked with a shifted balance between the phosphorylation status of STAT3 and STAT5, intracellular ROS levels, and STAT5 SUMOylation/de-SUMOylation. STAT5 emerged as a definitive negative regulator of xCT at the transcriptional level, while STAT3 activation is coupled with increased system xc- activity. We propose that careful classification of a patient's breast cancer subtype is central to effectively targeting STAT3/5 as a therapeutic means of treating breast cancer, particularly given that xCT is emerging as an important biomarker of aggressive cancers.
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
authors: Katja
authors: K
authors: Linher-Melville
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
authors: Mina G
authors: MG
authors: Nashed
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
authors: Robert G
authors: RG
authors: Ungard
authors: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada.
authors: Sina
authors: S
authors: Haftchenary
authors: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada.
authors: David A
authors: DA
authors: Rosa
authors: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada.
authors: Patrick T
authors: PT
authors: Gunning
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
authors: Gurmit
authors: G
authors: Singh
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D027182:Amino Acid Transport System y+; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D025841:Small Ubiquitin-Related Modifier Proteins