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Novel selective TOPK inhibitor SKLB-C05 inhibits colorectal carcinoma growth and metastasis
- Source :
- Cancer Letters. 445:11-23
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- The mitogen-activated protein kinase (MAPK) signaling pathway member T-LAK cell–originated protein kinase/PDZ-binding kinase (TOPK/PBK) is closely involved in tumorigenesis and progression. Its overexpression in colorectal carcinoma (CRC) exacerbates tumor malignancy, promotes metastasis and results in dismal prognosis. Therefore, targeting TOPK is a promising approach for CRC therapy. Here, we report the development of a TOPK selective inhibitor SKLB-C05, with subnanomolar inhibitory potency. In vitro, SKLB-C05 exhibited excellent cytotoxicity and anti-migration and invasion activity on TOPK high-expressing CRC cells and induced cell apoptosis. These activities could attribute to its inhibition of TOPK downstream signaling including extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1, 2, and 3 (JNK1/2/3), as well as downregulation of FAK/Src- MMP signaling. Furthermore, SKLB-C05 disrupted cell mitosis and blocked CRC cell cycle. In vivo, oral administration of SKLB-C05 at concentrations of 20 and 10 mg kg−1·day−1 dramatically attenuated CRC tumor xenograft growth and completely suppressed hepatic metastasis of HCT116 cells, respectively. Thus, these findings suggest that SKLB-C05 is a specific TOPK inhibitor with potent anti-CRC oncogenic activity in vitro and in vivo.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cancer Research
Lung Neoplasms
Cell Survival
MAP Kinase Signaling System
p38 mitogen-activated protein kinases
Cell
Administration, Oral
Mice
03 medical and health sciences
0302 clinical medicine
Cell Movement
Cell Line, Tumor
medicine
Animals
Humans
Protein kinase A
Protein Kinase Inhibitors
Cell Proliferation
Mitogen-Activated Protein Kinase Kinases
Chemistry
Kinase
Cell Cycle
Cell cycle
HCT116 Cells
Xenograft Model Antitumor Assays
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer research
Signal transduction
Colorectal Neoplasms
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 03043835
- Volume :
- 445
- Database :
- OpenAIRE
- Journal :
- Cancer Letters
- Accession number :
- edsair.doi.dedup.....15ad7bf23203862e572031452888c3dc