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

ABSTRACT: AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing ? and regulatory ? and ? subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPK?1 expression is relatively consistent across colon cancer cell lines, AMPK?1 depletion does not induce cell death. Conversely, AMPK?2 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.

SUBMITTER: Das B

PROVIDER: S-EPMC5830883 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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

Das Binita B Neilsen Beth K BK Fisher Kurt W KW Gehring Drew D Hu Youcai Y Volle Deanna J DJ Kim Hyun Seok HS McCall Jamie L JL Kelly David L DL MacMillan John B JB White Michael A MA Lewis Robert E RE

Scientific reports 20180228 1

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 ...[more]

PMID: 29491475

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Dataset Information

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

Publications

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

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