Selective activation of tumor-suppressive MAPKP signaling pathway by triptonide effectively inhibits pancreatic cancer cell tumorigenicity and tumor growth.

Selective activation of tumor-suppressive MAPKP signaling pathway by triptonide effectively inhibits pancreatic cancer cell tumorigenicity and tumor growth. Biochem Pharmacol. 2019 May 07;: Authors: Zhang B, Meng M, Xiang S, Cao Z, Xu X, Zhao Z, Zhang T, Chen B, Yang P, Li Y, Zhou Q Abstract 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 acti...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research