title: Kazinol-E is a specific inhibitor of ERK that suppresses the enrichment of a breast cancer stem-like cell population.
abstract: Growing evidence shows that cancer stem-like cells (CSLCs) contribute to breast cancer recurrence and to its resistance to conventional therapies. The extracellular signal-regulated kinase (ERK) signaling pathway is a major determinant in the control of diverse cellular processes, including the maintenance of CSLCs. In this study, we found that Kazinol-E, an antioxidant flavan from Broussonetia kazinoki, decreased the CSLC population of a breast cancer cell line, MCF7. The CSLC population, characterized by CD44 high/CD24 low expression or by high Aldehyde dehydrogenase 1 activity, was decreased by a concentration of Kazinol-E that did not affect the growth of bulk-cultured MCF7 cells. Kazinol-E did not decrease EGF-induced ERK phosphorylation in CSLCs, but did block the phosphorylation of an ERK substrate, p90RSK2, at Thr359/Ser363. We further demonstrated that EGF-induced ERK activity was blocked by Kazinol-E in a wild-type K-Ras-expressing non-small cell lung cancer cell line H226B. An in vitro kinase assay with purified ERK1 and p90RSK2 as its substrate demonstrated a direct inhibition of ERK activity by Kazinol E. Additionally, a the molecular docking study provided putative binding modes of Kazinol-E into the ATP binding pocket of ERK1 Collectively, these results suggest that Kazinol-E is a direct inhibitor of ERK1, and more studies are warranted to develop this reagent for therapeutic breast CSLC targeting.
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Yu-Chae
authors.initials: YC
authors.lastname: Jung
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Seula
authors.initials: S
authors.lastname: Han
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Li
authors.initials: L
authors.lastname: Hua
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Yeon-Hwa
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Cho
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Republic of Korea.
authors.forename: Cheol-Jung
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Hani
authors.initials: H
authors.lastname: Lee
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Republic of Korea.
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Jae-Ha
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Raok
authors.initials: R
authors.lastname: Jeon
authors.affiliation: The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea. Electronic address: wykim@sookmyung.ac.kr.
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Kim
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005419:Flavonoids / Q000008:administration & dosage*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*
chemical_list: D005419:Flavonoids; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Breast cancer stem cell; Extracellular signal-regulated kinase (ERK) pathway; Kazinol-E