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MUC1 activates JNK1 and inhibits apoptosis under genotoxic stress
Qiongqiong Chen1, Decai Li, Jian Ren
1Center for Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
Abstract:
The MUC1 transmembrane glycoprotein is aberrantly overexpressed in diverse human carcinomas and has been shown to inhibit apoptosis induced by genotoxic agents. In the present work, we report that MUC1 binds to and activates JNK1, an important member of the mitogen-activated protein kinases (MAPK) superfamily. The physical interaction between MUC1 cytoplasmic domain (MUC1-CD) and JNK1 was established by GST-pull-down assay in vitro and co-immunoprecipitation assay in vivo. We show that MUC1 activates JNK1 and inhibits cisplatin-induced apoptosis in human colon cancer HCT116 cells. Pharmacological inhibition of JNK or knockdown of JNK significantly reduces the ability of MUC1 to inhibit cisplatin-induced apoptosis. Together, our data indicate that MUC1 can inhibit apoptosis via activating JNK1 pathway in response to genotoxic anticancer agents.
Insights
MUC1 glycoprotein activates JNK1, a key kinase, to prevent cancer cell death from chemotherapy. This MUC1-JNK1 pathway offers a new target for cancer treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Aberrant MUC1 glycoprotein overexpression is common in human carcinomas.
- MUC1 is known to inhibit apoptosis induced by genotoxic agents.
Purpose of the Study:
- To investigate the mechanism by which MUC1 inhibits apoptosis.
- To determine if MUC1 interacts with and activates JNK1, a mitogen-activated protein kinase (MAPK).
Main Methods:
- GST-pull-down assays to confirm in vitro interaction between MUC1 cytoplasmic domain (MUC1-CD) and JNK1.
- Co-immunoprecipitation assays to confirm in vivo physical interaction.
- Assays in human colon cancer HCT116 cells to assess MUC1's effect on cisplatin-induced apoptosis.
- Pharmacological inhibition and knockdown of JNK to evaluate its role.
Main Results:
- MUC1 physically binds to and activates JNK1.
- MUC1 activation of JNK1 inhibits cisplatin-induced apoptosis in colon cancer cells.
- Inhibition or knockdown of JNK significantly diminishes MUC1's anti-apoptotic effect.
Conclusions:
- MUC1 inhibits apoptosis induced by genotoxic anticancer agents through the activation of the JNK1 pathway.
- The MUC1-JNK1 interaction represents a novel mechanism of cancer cell survival.
- Targeting the MUC1-JNK1 pathway may offer therapeutic strategies for overcoming chemoresistance.
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