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

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• 作者：Rae-Kwon Kim ; Yongjoon Suh ; Eun-Jung Lim ; Ki-Chun Yoo ; Ga-Haeng Lee ; Yan-Hong Cui ; Arang Son ; Eunji Hwang ; Nizam Uddin ; Joo-Mi Yi ; Seok-Gu Kang ; Su-Jae Lee
• 关键词：¦Á-Pyrone derivative ; Malignant progression ; Ras signaling pathway ; Invasion ; Migration ; Epithelial&ndash ; mesenchymal transition
• 刊名：Cancer Letters
• 出版年：2013
• 出版时间：28 August, 2013
• 年：2013
• 卷：337
• 期：1
• 页码：49-57
• 全文大小：1656 K

文摘

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