Journal
CANCER LETTERS
Volume 337, Issue 1, Pages 49-57Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2013.05.023
Keywords
alpha-Pyrone derivative; Malignant progression; Ras signaling pathway; Invasion; Migration; Epithelial-mesenchymal transition
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Funding
- National Research Foundation (NRF)
- Ministry of Education, Science and Technology (MEST), Korean government, through its National Nuclear Technology Program [2012M2A2A7035878]
- Converging Research Center Program Grant [2011K000877]
- Ministry of Education, Science, and Technology
- National Research Foundation of Korea [2012M2A2A7035878] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Elevated KRAS expression has been frequently associated with cancer progression including breast cancer; however, therapeutic approaches targeting KRAS have been widely unsuccessful and KRAS mutant cancers remain unsolved problem in cancer therapy. In this study, we found that a new 2-pyrone derivative, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP) can block KRAS-driven breast cancer progression. Importantly, treatment with BHP effectively suppressed the migratory and invasive properties along with epithelial-mesenchymal transition (EMT) in MDA-MB231 breast cancer cells that carry oncogenic KRAS and mesenchymal malignant phenotypes. In parallel, BHP also sensitized the cells to anticancer treatment. Consistently, forced-expression of oncogenic KRAS bestowed the migratory and invasive properties, mesenchymal transition and resistance to anticancer treatment into normal human mammalian breast cells MCF10A and relatively non-malignant MCF7 and SK-BR3 breast cancer cells; however, treatment with BHP blocked those KRAS-induced malignant phenotypes. Notably, BHP interfered the interaction of KRAS with Raf-1 in concentration-dependent manner, thereby blocking the downstream effectors of KRAS signaling that is PI3K/AKT and ERK. Taken together, our findings indicate that the BHP, an alpha-pyrone derivative, suppresses malignant breast cancer progression by targeting of oncogenic KRAS signaling pathways. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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