![]() Despite substantial efforts to develop therapeutics targeting this pathway 4, 5, significant challenges still exist. The Ras oncogene is activated in more than 40% of colon tumors 1 and 25%-30% of human cancers overall 2, 3. ![]() 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. Human colon cancer cell lines are notably more sensitive to 5′-hydroxy-staurosporine than are non-transformed human colon epithelial cells. FUSION identified 5′-hydroxy-staurosporine, which competitively inhibits AMPK. 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. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA-mediated depletion induces cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. ![]() Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. ![]() AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits.
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