title: Targeting SOD1 induces synthetic lethal killing in BLM- and CHEK2-deficient colorectal cancer cells.
abstract: Cancer is a major cause of death throughout the world, and there is a large need for better and more personalized approaches to combat the disease. Over the past decade, synthetic lethal approaches have been developed that are designed to exploit the aberrant molecular origins (i.e. defective genes) that underlie tumorigenesis. BLM and CHEK2 are two evolutionarily conserved genes that are somatically altered in a number of tumor types. Both proteins normally function in preserving genome stability through facilitating the accurate repair of DNA double strand breaks. Thus, uncovering synthetic lethal interactors of BLM and CHEK2 will identify novel candidate drug targets and lead chemical compounds. Here we identify an evolutionarily conserved synthetic lethal interaction between SOD1 and both BLM and CHEK2 in two distinct cell models. Using quantitative imaging microscopy, real-time cellular analyses, colony formation and tumor spheroid models we show that SOD1 silencing and inhibition (ATTM and LCS-1 treatments), or the induction of reactive oxygen species (2ME2 treatment) induces selective killing within BLM- and CHEK2-deficient cells relative to controls. We further show that increases in reactive oxygen species follow SOD1 silencing and inhibition that are associated with the persistence of DNA double strand breaks, and increases in apoptosis. Collectively, these data identify SOD1 as a novel candidate drug target in BLM and CHEK2 cancer contexts, and further suggest that 2ME2, ATTM and LCS-1 are lead therapeutic compounds warranting further pre-clinical study.
authors: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.|Research Institute of Oncology and Hematology, Winnipeg, Manitoba, Canada.
authors: Babu V
authors: BV
authors: Sajesh
authors: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.|Research Institute of Oncology and Hematology, Winnipeg, Manitoba, Canada.
authors: Kirk J
authors: KJ
authors: McManus
mesh_terms: D000077584:2-Methoxyestradiol; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008982:Molybdenum / Q000494:pharmacology; D034741:RNA, Small Interfering; D053484:RecQ Helicases / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; C000606290:SOD1 protein, human; D004958:Estradiol; D000077584:2-Methoxyestradiol; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: BLM; CHEK2; SOD1; drug targeting; synthetic lethality