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Discovery of a novel dual-target inhibitor against RSK1 and MSK2 to suppress growth of human colon cancer.
- Source :
-
Oncogene [Oncogene] 2020 Oct; Vol. 39 (43), pp. 6733-6746. Date of Electronic Publication: 2020 Sep 22. - Publication Year :
- 2020
-
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.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents therapeutic use
Apoptosis
Cell Line, Tumor
Colonic Neoplasms pathology
Crystallography, X-Ray
Drug Discovery
Female
HEK293 Cells
Humans
Mice
Molecular Docking Simulation
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors therapeutic use
Ribosomal Protein S6 Kinases, 90-kDa metabolism
Ribosomal Protein S6 Kinases, 90-kDa ultrastructure
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Colonic Neoplasms drug therapy
Protein Kinase Inhibitors pharmacology
Ribosomal Protein S6 Kinases, 90-kDa antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 39
- Issue :
- 43
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 32963350
- Full Text :
- https://doi.org/10.1038/s41388-020-01467-w