title: Oxidized ATM promotes abnormal proliferation of breast CAFs through maintaining intracellular redox homeostasis and activating the PI3K-AKT, MEK-ERK, and Wnt-β-catenin signaling pathways.
abstract: Abnormal proliferation is one characteristic of cancer-associated fibroblasts (CAFs), which play a key role in tumorigenesis and tumor progression. Oxidative stress (OS) is the root cause of CAFs abnormal proliferation. ATM (ataxia-telangiectasia mutated protein kinase), an important redox sensor, is involved in DNA damage response and cellular homeostasis. Whether and how oxidized ATM regulating CAFs proliferation remains unclear. In this study, we show that there is a high level of oxidized ATM in breast CAFs in the absence of double-strand breaks (DSBs) and that oxidized ATM plays a critical role in CAFs proliferation. The effect of oxidized ATM on CAFs proliferation is mediated by its regulation of cellular redox balance and the activity of the ERK, PI3K-AKT, and Wnt signaling pathways. Treating cells with antioxidant N-acetyl-cysteine (NAC) partially rescues the proliferation defect of the breast CAFs caused by ATM deficiency. Administrating cells with individual or a combination of specific inhibitors of the ERK, PI3K-AKT, and Wnt signaling pathways mimics the effect of ATM deficiency on breast CAF proliferation. This is mainly ascribed to the β-catenin suppression and down-regulation of c-Myc, thus further leading to the decreased cyclinD1, cyclinE, and E2F1 expression and the enhanced p21(Cip1) level. Our results reveal an important role of oxidized ATM in the regulation of the abnormal proliferation of breast CAFs. Oxidized ATM could serve as a potential target for treating breast cancer.
authors.affiliation: a Key Laboratory of Laboratory Medical Diagnostics; Chinese Ministry of Education; Chongqing Medical University ; Chongqing , China.
authors.forename: Shifu
authors.initials: S
authors.lastname: Tang
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Hou
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Tu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Sun
authors.forename: Lei
authors.initials: L
authors.lastname: Lang
authors.forename: Xi
authors.initials: X
authors.lastname: Tang
authors.forename: Yan-E
authors.initials: YE
authors.lastname: Du
authors.forename: Mingli
authors.initials: M
authors.lastname: Zhou
authors.forename: Tenghua
authors.initials: T
authors.lastname: Yu
authors.forename: Liyun
authors.initials: L
authors.lastname: Xu
authors.forename: Siyang
authors.initials: S
authors.lastname: Wen
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
authors.forename: Manran
authors.initials: M
authors.lastname: Liu
mesh_terms: D000975:Antioxidants / Q000737:chemistry; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053903:DNA Breaks, Double-Stranded; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000975:Antioxidants; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D010100:Oxygen
keywords: ATM, ataxia telangiectasia mutated; CAFs, cancer associated fibroblasts; CCNA2, cyclin A2; CCNB2, cyclin B2; CDK1, cyclin-dependent kinase 1; CDKN2B, cyclin-dependent kinase inhibitor 2B; DSBs, double strand breaks; E2F1, E2F transcription factor 1; NAC, N-acetyl-cysteine; NFs, normal fibroblasts; OS, oxidative stress; ROS, reactive oxygen species; TM, tumor microenvironment; abnormal proliferation; breast cancer; cancer-associated fibroblasts; oxidative stress; oxidized ATM; proliferation signaling pathways; reactive oxygen species; redox homeostasis