The T-LAK Cell-originated Protein Kinase Signal Pathway Promotes Colorectal Cancer Metastasis

Autor: Ke Yao, Do Young Lim, Zigang Dong, Feng Zhu, Tatyana A. Zykova, Haitao Li, Ruihua Bai, Lei Wang, Ann M. Bode
Rok vydání: 2016
Předmět:
0301 basic medicine
Kinase
Colorectal cancer
TOPK
SOS
Son of Sevenless
lcsh:Medicine
Mitogen-activated protein kinase kinase
Metastasis
Mice
RSK2
ribosomal S6 kinase 2
Cell Movement
Phosphorylation
JNK1/2
c-Jun N-terminal kinase 1/2
Cdk1/cyclin B
cyclin dependent kinase 1/cyclin B1
Gene knockdown
lcsh:R5-920
Liver Neoplasms
Intracellular Signaling Peptides and Proteins
General Medicine
3. Good health
CRC
colorectal cancer
Adenocarcinoma
RNA Interference
lcsh:Medicine (General)
Colorectal Neoplasms
HT29 Cells
Protein Binding
Signal Transduction
Research Paper
MSK1
mitogen and stress activated kinase 1
Recombinant Fusion Proteins
Mice
Nude
Biology
Protein Serine-Threonine Kinases
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Cell Line
Tumor
medicine
ERK1/2
extracellular signal-regulated kinase
Animals
Humans
Protein kinase A
Mitogen-Activated Protein Kinase Kinases
EGF
epidermal growth factor
lcsh:R
Cancer
medicine.disease
HCT116 Cells
PRPK
030104 developmental biology
HEK293 Cells
Mutation
Cancer research
MAPKK
mitogen-activated protein kinase
MAPK
mitogen-activated protein kinase
MEK
mitogen-activated protein kinase
Zdroj: EBioMedicine
EBioMedicine, Vol 18, Iss C, Pp 73-82 (2017)
ISSN: 2352-3964
Popis: Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. Metastasis is the most lethal attribute of colorectal cancer. New data regarding the molecules contributing to the metastatic phenotype, the pathways they control and the genes they regulate are very important for understanding the processes of metastasis prognosis and prevention in the clinic. The purpose of this study was to investigate the role of T-LAK cell-originated protein kinase (TOPK) in the promotion of colorectal cancer metastasis. TOPK is highly expressed in human metastatic colorectal cancer tissue compared with malignant adenocarcinoma. We identified p53-related protein kinase (PRPK) as a new substrate of TOPK. TOPK binds with and phosphorylates PRPK at Ser250 in vitro and ex vivo. This site plays a critical role in the function of PRPK. Cell lines stably expressing mutant PRPK (S250A), knockdown TOPK, knockdown PRPK or knockdown of both TOPK and PRPK significantly inhibited liver metastasis of human HCT116 colon cancer cells in a xenograft mouse model. Therefore, we conclude that TOPK directly promotes metastasis of colorectal cancer by modulating PRPK. Thus, these findings may assist in the prediction of prognosis or development of new therapeutic strategies against colon cancer.
Highlights • Knockdown of TOPK or PRPK significantly inhibits liver metastasis of human colon cancer cells in vivo. • PRPK is a newly identified substrate of TOPK and TOPK, but not Akt, phosphorylates PRPK at Ser250. • Phosphorylation Ser250 is important for the function of PRPK in promoting liver metastasis of colon cancer cells in vivo. Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Identifying new mechanisms contributing to metastasis of colon cancer cells to the liver is important for finding novel targets for chemotherapy. T-LAK-cell-originated protein kinase (TOPK) is a valuable prognostic marker in patients with sporadic CRC and 30–40% of CRC patients may benefit from the inhibition of TOPK. We identified p53-related protein kinase (PRPK) as a novel substrate for TOPK. The TOPK/PRPK signaling axis is directly involved in colon metastasis to the liver and its inhibition could lead to effective anti-metastatic therapies in patients with colon cancer.
Databáze: OpenAIRE
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