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Cancer Lett. 2013 Aug 28;337(1):49-57. doi: 10.1016/j.canlet.2013.05.023. Epub 2013 May 23.

A novel 2-pyrone derivative, BHP, impedes oncogenic KRAS-driven malignant progression in breast cancer.

Author information

1
Department of Chemistry, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.

Abstract

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 α-pyrone derivative, suppresses malignant breast cancer progression by targeting of oncogenic KRAS signaling pathways.

KEYWORDS:

Epithelial–mesenchymal transition; Invasion; Malignant progression; Migration; Ras signaling pathway; α-Pyrone derivative

PMID:
23707634
DOI:
10.1016/j.canlet.2013.05.023
[Indexed for MEDLINE]

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