A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells

Scientific Reports
Binita DasRobert E Lewis

Abstract

AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA-mediated depletion induces cell death. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. We used Functional Signature Ontology (FUSION) to screen a natural product library to identify compounds that were inhibitors of AMPK to test its potential for detecting small molecules with preferential toxicity toward human colon tumor cells. FUSION identified 5'-hydroxy-staurosporine, which competitively inhibits AMPK. Human colon cancer cell lines are notably more sensitive to 5'-hydroxy-staurosporine than are non-transformed human colon epithelial cells. This study serves as proof-of-concept for unbiased FUSION-based detection of small molecule inhibitors o...Continue Reading

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Citations

Oct 26, 2018·The Journal of General Physiology·Michael A KalwatMelanie H Cobb
Jun 13, 2019·Natural Product Reports·Lindsay K Caesar, Nadja B Cech
Aug 29, 2018·Scientific Reports·Jason M CorrentiRotonya M Carr
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Methods Mentioned

BETA
flow cytometry
nuclear magnetic resonance
protein assay
Assay

Software Mentioned

Fu Si gnature On tology ( FUSION )
FUSION

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