Targeting SOD1 induces synthetic lethal killing in BLM- and CHEK2-deficient colorectal cancer cells

Oncotarget
Babu V Sajesh, Kirk J McManus

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 ...Continue Reading

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Citations

Oct 19, 2017·Viruses·Robert A KozakGary P Kobinger
Nov 7, 2017·Cancers·Laura L ThompsonKirk J McManus
May 4, 2017·Cellular Oncology (Dordrecht)·Brent J Guppy, Kirk J McManus
Jul 18, 2018·Nature Methods·Nan Cher YeoGeorge M Church
Oct 13, 2020·Trends in Cancer·Arindam DattaRobert M Brosh
Oct 23, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Vinit C ShanbhagMichael J Petris

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Methods Mentioned

BETA
transfection

Software Mentioned

GraphPad
ImageJ
InSphero
Prism
GEN5

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