A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer.

Do Young Lim,Igor Kurinov,Yibin Deng,Kun Yeong Lee,Bu Young Choi,Seung Ho Shin,Ki Beom Bae,Kangdong Liu,Zigang Dong,Margarita Malakhova,Yanan Jiang,Jinglong Xu,Qiong Wu,Ziming Dong,Mee-Hyun Lee,Ann Bode

doi:10.18632/oncotarget.9223

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.

Highlights

Lung cancer is a devastating disease with very low 5-year survival rate (17%) compared to other major types of cancers, including breast (89%), prostate (99%) and colorectal (65%)
The results of the MTS assay showed that catechol was not toxic to the normal NL20 lung cell line (Figure 1B), but inhibited the anchorage-independent growth of various types of lung cancer cells, including murine KP2 and human H460 cells (Figure 1C, Supplementary Figure 1)
Because the catechol moiety is a part of these two molecules, we hypothesized that catechol could have binding affinity with extracellular signal-regulated kinase 2 (ERK2)

Summary

Introduction

Lung cancer is a devastating disease with very low 5-year survival rate (17%) compared to other major types of cancers, including breast (89%), prostate (99%) and colorectal (65%). It has been the leading cause of cancer death in men and women since the 1950s and 1980s, respectively [1]. Epidemiological studies showed that many risk factors, such as smoking, alcohol and asbestos, are closely related to lung carcinogenesis. ERK is a signaling molecule commonly activated by risk factors of lung cancer including smoking [3], alcohol [4], and asbestos [5]. ERK directly binds and phosphorylates c-Myc at Ser resulting in c-Myc activation and enhanced protein stability [6, 8]

Methods

Results

Conclusion