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

Authors
 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 
Citation
 CANCER LETTERS, Vol.337(1) : 49-57, 2013 
Journal Title
 CANCER LETTERS 
ISSN
 0304-3835 
Issue Date
2013
MeSH
Antineoplastic Agents/pharmacology* ; Breast Neoplasms/drug therapy* ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Disease Progression ; Epithelial-Mesenchymal Transition ; Female ; Humans ; Neoplasm Invasiveness ; Proto-Oncogene Proteins/antagonists & inhibitors* ; Proto-Oncogene Proteins p21(ras) ; Pyrones/pharmacology* ; ras Proteins/antagonists & inhibitors*
Keywords
Epithelial–mesenchymal transition ; Invasion ; Malignant progression ; Migration ; Ras signaling pathway ; α-Pyrone derivative
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.
Full Text
http://www.sciencedirect.com/science/article/pii/S0304383513004059
DOI
10.1016/j.canlet.2013.05.023
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/87061
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