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

Authors
 Binita Das  ;  Beth K Neilsen  ;  Kurt W Fisher  ;  Drew Gehring  ;  Youcai Hu  ;  Deanna J Volle  ;  Hyun Seok Kim  ;  Jamie L McCall  ;  David L Kelly  ;  John B MacMillan  ;  Michael A White  ;  Robert E Lewis 
Citation
 Scientific Reports, Vol.8(1) : 3770, 2018 
Journal Title
 Scientific Reports 
Issue Date
2018
Abstract
AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing alpha and regulatory beta and gamma subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKalpha1 expression is relatively consistent across colon cancer cell lines, AMPKalpha1 depletion does not induce cell death. Conversely, AMPKalpha2 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 of therapeutic targets and highlights its potential to identify novel compounds for cancer therapy development.
Files in This Item:
T201801192.pdf Download
DOI
10.1038/s41598-018-22090-6
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/162251
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