title: A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer.
abstract: Various carcinogens induce EGFR/RAS/MAPK signaling, which is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 in lung carcinogenesis could be beneficial. We examined the therapeutic effect of catechol in lung cancer treatment. Catechol suppressed anchorage-independent growth of murine KP2 and human H460 lung cancer cell lines in a dose-dependent manner. Catechol inhibited ERK2 kinase activity in vitro, and its direct binding to the ERK2 active site was confirmed by X-ray crystallography. Phosphorylation of c-Myc, a substrate of ERK2, was decreased in catechol-treated lung cancer cells and resulted in reduced protein stability and subsequent down-regulation of total c-Myc. Treatment with catechol induced G1 phase arrest in lung cancer cells and decreased protein expression related to G1-S progression. In addition, we showed that catechol inhibited the growth of both allograft and xenograft lung cancer tumors in vivo. In summary, catechol exerted inhibitory effects on the ERK2/c-Myc signaling axis to reduce lung cancer tumor growth in vitro and in vivo, including a preclinical patient-derived xenograft (PDX) model. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis in future clinical approaches.
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.
authors.forename: Do Young
authors.initials: do Y
authors.lastname: Lim
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.|Program in Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Shin
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.|The China-US (Henan) Cancer Institute, Zhengzhou, Henan, China.
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Malakhova
authors.affiliation: Cornell University, NE-CAT, Argonne, IL, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Kurinov
authors.affiliation: The China-US (Henan) Cancer Institute, Zhengzhou, Henan, China.|The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Hunan, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Hunan, China.|The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Jinglong
authors.initials: J
authors.lastname: Xu
authors.affiliation: The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Hunan, China.|The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Hunan, China.|The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
authors.affiliation: The China-US (Henan) Cancer Institute, Zhengzhou, Henan, China.|The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Hunan, China.|The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China.|The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.
authors.forename: Kun Yeong
authors.initials: KY
authors.lastname: Lee
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.
authors.forename: Ki Beom
authors.initials: KB
authors.lastname: Bae
authors.affiliation: Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Cheongju, Chungbuk, South Korea.
authors.forename: Bu Young
authors.initials: BY
authors.lastname: Choi
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Deng
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, MN, USA.|The China-US (Henan) Cancer Institute, Zhengzhou, Henan, China.|The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Hunan, China.|The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China.|The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002396:Catechols; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; C034221:catechol
keywords: ERK2; c-Myc; catechol; lung cancer; natural compound