title: Down-regulation of MsrB3 induces cancer cell apoptosis through reactive oxygen species production and intrinsic mitochondrial pathway activation.
abstract: Methionine sulfoxide reductase B3 (MsrB3) is a protein repair enzyme that specifically catalyzes the reduction of methionine-R-sulfoxide residues and has an antioxidant function. We have previously shown that depletion of MsrB3 suppresses the proliferation of normal mammalian cells by arresting cell cycle. In this study, we report the crucial role of MsrB3 in cancer cell death. Deficiency of MsrB3 induced cancer cell death, while MsrB3 overexpression stimulated cancer cell proliferation. MsrB3 depletion resulted in apoptotic cancer cell death through the activation of the intrinsic mitochondrial pathway. MsrB3 deficiency increased the levels of cellular reactive oxygen species (ROS) and led to redox imbalance, and also increased the Bax to Bcl-2 ratio and cytochrome c release, leading to caspase activation. Treatment of MsrB3-depleted cells with N-acetylcysteine, an ROS scavenger, prevented cell death, suggesting that MsrB3 deficiency-induced cell death is associated with increased ROS production. In addition, MsrB3 depletion activated poly(ADP ribose) polymerase-1 (PARP-1) and led to the translocation of apoptosis-inducing factor (AIF) to the nucleus. Taken together, our results suggest that MsrB3 plays an important role in cancer cell survival through the modulation of the intrinsic apoptosis pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea.
authors.forename: Geun-Hee
authors.initials: GH
authors.lastname: Kwak
authors.affiliation: Department of Biochemistry, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea. Electronic address: hykim@ynu.ac.kr.
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000072283:A549 Cells; D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D051150:Methionine Sulfoxide Reductases / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D017382:Reactive Oxygen Species; D051150:Methionine Sulfoxide Reductases; C524352:MSRB3 protein, human; D000111:Acetylcysteine
keywords: Cancer; Cell death; Methionine sulfoxide; MsrB3; Redox imbalance