Document Type
Article
Publication Date
2018
College/Unit
School of Medicine
Department/Program/Center
Medicine
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 of therapeutic targets and highlights its potential to identify novel compounds for cancer therapy development.
Digital Commons Citation
Das, Binita; Neilsen, Beth K.; Fisher, Kurt W.; Gehring, Drew; Hu, Youcai; Volle, Deanna J.; Kim, Hyun Seok; McCall, Jamie L.; Kelly, David L.; MacMillian, John B.; White, Michael A.; and Lewis, Robert E., "A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells" (2018). Faculty & Staff Scholarship. 1827.
https://researchrepository.wvu.edu/faculty_publications/1827
Source Citation
Das, B., Neilsen, B. K., Fisher, K. W., Gehring, D., Hu, Y., Volle, D. J., Kim, H. S., McCall, J. L., Kelly, D. L., MacMillan, J. B., White, M. A., & Lewis, R. E. (2018). A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-22090-6
Included in
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Comments
Open Access This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre- ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per- mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2018