Selective activation of tumor-suppressive MAPKP signaling pathway by triptonide effectively inhibits pancreatic cancer cell tumorigenicity and tumor growth
Autor: | Mei Meng, Zhifei Cao, Xing-dong Xu, Zhe Zhao, Quansheng Zhou, Tong Zhang, Bowen Chen, Ping Yang, Ye Li, Bin Zhang, Shufen Xiang |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Carcinogenesis MAP Kinase Signaling System p38 mitogen-activated protein kinases Mice SCID medicine.disease_cause Biochemistry 03 medical and health sciences Mice Random Allocation 0302 clinical medicine medicine Animals Humans ASK1 Protein kinase A Pharmacology Mitogen-Activated Protein Kinase Kinases Mice Inbred NZB Gadd45 Chemistry Kinase Xenograft Model Antitumor Assays Triterpenes Tumor Burden Enzyme Activation Pancreatic Neoplasms 030104 developmental biology Treatment Outcome 030220 oncology & carcinogenesis Cancer research Female Signal transduction |
Zdroj: | Biochemical pharmacology. 166 |
ISSN: | 1873-2968 |
Popis: | The mitogen-activated protein kinase (MAPK, 1K) family members ERK, JNK, and p38 play a divergent role in either promoting tumorigenesis or tumor-suppression. Activation of ERK and JNK promotes tumorigenesis; whereas, escalation of p38 inhibits carcinogenesis. As these three MAPK members are controlled by the common up-stream MAPK signaling proteins which consist of MAPK kinases (2K) and MAPK kinase kinases (3K), how to selectively actuate tumor-suppressive p38, not concurrently stimulate tumorigenic ERK and JNK, in cancer cells is a challenge for cancer researchers, and a new opportunity for novel anti-cancer drug discovery. Using human pancreatic cancer cells and xenograft mice as models, we found that a small molecule triptonide first discerningly activated the up-stream MAPK kinase kinase MEKK4, not the other two 3K members ASK1 and GADD45; and then selectively actuated the middle stream MAPK kinase MKK4, not the other two 2K members MKK3 and MKK6; and followed by activation of the MAPK member p38, not the other two members ERK and JNK. These data suggest that triptonide is a selective MEKK4-MKK4-p38 axis agonist. Consequently, selective activation of the MEKK4-MKK4-p38 signaling axis by triptonide activated tumor suppressor p21 and inhibited CDK3 expression, resulting in cancer cell cycle arrest at G2/M phase and marked inhibition of pancreatic cancer cell tumorigenic capability in vitro and tumor growth in xenograft mice. Our findings support the notion that selective activation of tumor-suppressive MEKK4-MKK4-p38-p21signaling pathway by triptonide is a new approach for pancreatic cancer therapy, providing a new drug candidate for development of novel anti-cancer therapeutics. |
Databáze: | OpenAIRE |
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