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: Do Young Lim, Seung Ho Shin, Mee-Hyun Lee, Margarita Malakhova, Igor Kurinov, Qiong Wu, Jinglong Xu, Yanan Jiang, Ziming Dong, Kangdong Liu, Kun Yeong Lee, Ki Beom Bae, Bu Young Choi, Yibin Deng, Ann Bode, Zigang Dong
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 23 Pg. 35001-14 (Jun 07 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27167001 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Catechols
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• catechol

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Catechols (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Mice
• Mice, Nude
• Mice, SCID
• Mitogen-Activated Protein Kinase 1 (drug effects, metabolism)
• Proto-Oncogene Proteins c-myc (drug effects, metabolism)
• Xenograft Model Antitumor Assays