A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer
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Do Young Lim1, Seung Ho Shin1,2, Mee-Hyun Lee1,3, Margarita Malakhova1, Igor Kurinov4, Qiong Wu3,5, Jinglong Xu5,7, Yanan Jiang5,7, Ziming Dong5,7, Kangdong Liu3,5,6,7, Kun Yeong Lee1, Ki Beom Bae1, Bu Young Choi8, Yibin Deng1, Ann Bode1, Zigang Dong1,3,5,6,7
1The Hormel Institute, University of Minnesota, MN, USA
2Program in Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, MN, USA
3The China-US (Henan) Cancer Institute, Zhengzhou, Henan, China
4Cornell University, NE-CAT, Argonne, IL, USA
5The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Hunan, China
6The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China
7The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
8Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Cheongju, Chungbuk, South Korea
Zigang Dong, email: firstname.lastname@example.org
Keywords: catechol, lung cancer, ERK2, c-Myc, natural compound
Received: January 06, 2016 Accepted: April 10, 2016 Published: May 07, 2016
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.
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