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

Oncogene volume 39, pages 6733–6746 (2020)Cite this article

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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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Fig. 1: RSK1 and MSK2 are highly expressed in colon cancer tissues and cells.
Fig. 2: RSK1 and MSK2 are the potential target of colon cancer.
Fig. 3: Knocking down RSK1 and MSK2 expression in colon cancer induces apoptosis.
Fig. 4: APIO-EE-07 directly binds to RSK1 and MSK2.
Fig. 5: APIO-EE-07, a dual inhibitor of RSK1 and MSK2, suppresses colon cancer cell growth and anchorage-independent growth.
Fig. 6: APIO-EE-07, a dual inhibitor of RSK1 and MSK2, induces colon cancer apoptosis.
Fig. 7: APIO-EE-07, a dual inhibitor of RSK1 and MSK2, attenuated colon cancer patient-derived xenograft (PDX) growth in vivo.
Fig. 8: The signaling pathway of APIO-EE-07 induced apoptosis in colon cancer.

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Funding

This work was supported by the Key Science and Technology Program of Henan Province, China (182102310125) and the Key program of TCM research in Henan Province, China (2018ZY1016, 2019ZY1037).

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Author notes

  1. These authors have contributed equally: Guoguo Jin, Mingyang Yan, Kangdong Liu

Authors and Affiliations

  1. The Henan Luoyang Orthopedic Hospital, Zhengzhou, Henan, People’s Republic of China

    Guoguo Jin & Zhiping Guo

  2. China-US (Henan) Hormel Cancer Institute, Zhengzhou, People’s Republic of China

    Guoguo Jin, Mingyang Yan, Kangdong Liu, Dhilli Rao Gorja, Kyle Vaughn Laster & Zigang Dong

  3. Henan Provincial Cooperative Innovation Center of Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    Guoguo Jin & Kangdong Liu

  4. Pathophysiology Department, School of Basic Medical Science, College of Medicine Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    Kangdong Liu & Zigang Dong

  5. The Hormel Institute, University of Minnesota, Austin, MN, USA

    Ke Yao, Hanyong Chen & Kanamata Reddy

  6. Center of Bio Repository, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    Chengjuan Zhang

  7. Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China

    Yang Yi

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Contributions

GJ, KY, ZG, and ZD designed this study. GJ, MY, and KL performed the experiment, analyzed data, and prepared figures. KD and DG synthesis chemicals. HC contributed to computational analysis. KL analyzed of GEPIA database. ZJ and YY performed some explements. GJ wrote paper and ZD revised the paper.

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Correspondence to Zhiping Guo or Zigang Dong.

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Jin, G., Yan, M., Liu, K. et al. Discovery of a novel dual-target inhibitor against RSK1 and MSK2 to suppress growth of human colon cancer. Oncogene 39, 6733–6746 (2020). https://doi.org/10.1038/s41388-020-01467-w

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