title: Low-dose arsenic induces chemotherapy protection via p53/NF-κB-mediated metabolic regulation.
abstract: Most chemotherapeutical drugs kill cancer cells chiefly by inducing DNA damage, which unfortunately also causes undesirable injuries to normal tissues, mainly due to p53 activation. We report a novel strategy of normal tissue protection that involves p53/NF-κB coordinated metabolic regulation. Pretreatment of untransformed cells with low doses of arsenic induced concerted p53 suppression and NF-κB activation, which elicited a marked induction of glycolysis. Significantly, this metabolic shift provided cells effective protection against cytotoxic chemotherapy, coupling the metabolic pathway to cellular resistance. Using both in vitro and in vivo models, we demonstrated an absolute requirement of functional p53 in arsenic-mediated protection. Consistently, a brief arsenic pretreatment selectively protected only normal tissues, but not tumors, from toxicity of chemotherapy. An indispensable role of glycolysis in protecting normal tissues was demonstrated by using an inhibitor of glycolysis, 2-deoxyglucose, which almost totally abolished low-dose arsenic-mediated protection. Together, our work demonstrates that low-dose arsenic renders normal cells and tissues resistant to chemotherapy-induced toxicity by inducting glycolysis.
authors.affiliation: 1] Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ganapathy
authors.affiliation: Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Seo
authors.affiliation: Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lall
authors.affiliation: 1] Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shadfan
authors.affiliation: Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Ha
authors.affiliation: 1] Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Z-M
authors.initials: ZM
authors.lastname: Yuan
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001151:Arsenic / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D001151:Arsenic