title: A novel 2-pyrone derivative, BHP, impedes oncogenic KRAS-driven malignant progression in breast cancer.
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.
authors.affiliation: Department of Chemistry, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Rae-Kwon
authors.initials: RK
authors.lastname: Kim
authors.forename: Yongjoon
authors.initials: Y
authors.lastname: Suh
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lim
authors.forename: Ki-Chun
authors.initials: KC
authors.lastname: Yoo
authors.forename: Ga-Haeng
authors.initials: GH
authors.lastname: Lee
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Cui
authors.forename: Arang
authors.initials: A
authors.lastname: Son
authors.forename: Eunji
authors.initials: E
authors.lastname: Hwang
authors.forename: Nizam
authors.initials: N
authors.lastname: Uddin
authors.forename: Joo-Mi
authors.initials: JM
authors.lastname: Yi
authors.forename: Seok-Gu
authors.initials: SG
authors.lastname: Kang
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D016283:Proto-Oncogene Proteins p21(ras); D011753:Pyrones / Q000494:pharmacology*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: C572758:5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011753:Pyrones; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Epithelial–mesenchymal transition; Invasion; Malignant progression; Migration; Ras signaling pathway; α-Pyrone derivative