2. Academic Validation
  3. Discovery of a novel dual-target inhibitor against RSK1 and MSK2 to suppress growth of human colon cancer

Discovery of a novel dual-target inhibitor against RSK1 and MSK2 to suppress growth of human colon cancer

  • Oncogene. 2020 Oct;39(43):6733-6746. doi: 10.1038/s41388-020-01467-w.
Guoguo Jin  # 1 2 3,  Mingyang Yan  # 2,  Kangdong Liu  # 2 3 4,  Ke Yao 5,  Hanyong Chen 5,  Chengjuan Zhang 6,  Yang Yi 7,  Kanamata Reddy 5,  Dhilli Rao Gorja 2,  Kyle Vaughn Laster 2,  Zhiping Guo 8,  Zigang Dong 9 10
Affiliations

Affiliations

  • 1 The Henan Luoyang Orthopedic Hospital, Zhengzhou, Henan, People's Republic of China.
  • 2 China-US (Henan) Hormel Cancer Institute, Zhengzhou, People's Republic of China.
  • 3 Henan Provincial Cooperative Innovation Center of Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
  • 4 Pathophysiology Department, School of Basic Medical Science, College of Medicine Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
  • 5 The Hormel Institute, University of Minnesota, Austin, MN, USA.
  • 6 Center of Bio Repository, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
  • 7 Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan, People's Republic of China.
  • 8 The Henan Luoyang Orthopedic Hospital, Zhengzhou, Henan, People's Republic of China. [email protected].
  • 9 China-US (Henan) Hormel Cancer Institute, Zhengzhou, People's Republic of China. [email protected].
  • 10 Pathophysiology Department, School of Basic Medical Science, College of Medicine Zhengzhou University, Zhengzhou, Henan, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 32963350 DOI: 10.1038/s41388-020-01467-w
Abstract

Colon Cancer is the most aggressive tumor in both men and women globally. As many the chemotherapeutic regimens have adverse side effects and contribute to the resistance and recurrence, therefore, finding novel therapeutic targets and developing effective agents are urgent. Based on the TCGA and GTEx database analysis, RSK1 and MSK2 were found abnormal expressed in colon Cancer. RSK1 and MSK2 were overexpressed in colon Cancer tissues confirmed by western blot and IHC. After knocking down RSK1 or MSK2, cell proliferation and anchorage-independent cell growth were markedly inhibited. Using a computer docking model, we identified a novel dual-target inhibitor, APIO-EE-07, that could block both RSK1 and MSK2 kinase activity in a dose-dependent manner. APIO-EE-07 inhibited cell growth and induced Apoptosis and also increased expression of Bax as well as cleaved Caspase-3 and -PARP in colon Cancer cells by downregulating RSK1 and MSK2 downstream targets, including CREB and ATF1. Furthermore, APIO-EE-07 decreased tumor volume and weight in human patient-derived xenografts tumors implanted in SCID mice. In summary, our results demonstrate that RSK1 and MSK2 are the potential targets for the treatment of colon Cancer. APIO-EE-07, a novel dual-target inhibitor of RSK1 and MSK2, can suppress the growth of colon Cancer by attenuating RSK1 and MSK2 signaling.

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