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Updated: Jul 11, 2025
Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
A conserved mechanism for JNK-mediated loss of Notch function in advanced prostate cancer
Cheng-Wei Wang1,2, Marie Clémot1,2, Takao Hashimoto1
1Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
Abstract:
Dysregulated Notch signaling is a common feature of cancer; however, its effects on tumor initiation and progression are highly variable, with Notch having either oncogenic or tumor-suppressive functions in various cancers. To better understand the mechanisms that regulate Notch function in cancer, we studied Notch signaling in a Drosophila tumor model, prostate cancer-derived cell lines, and tissue samples from patients with advanced prostate cancer. We demonstrated that increased activity of the Src-JNK pathway in tumors inactivated Notch signaling because of JNK pathway-mediated inhibition of the expression of the gene encoding the Notch S2 cleavage protease, Kuzbanian, which is critical for Notch activity. Consequently, inactive Notch accumulated in cells, where it was unable to transcribe genes encoding its target proteins, many of which have tumor-suppressive activities. These findings suggest that Src-JNK activity in tumors predicts Notch activity status and that suppressing Src-JNK signaling could restore Notch function in tumors, offering opportunities for diagnosis and targeted therapies for a subset of patients with advanced prostate cancer.
Insights
In cancer, the Src-JNK pathway can inactivate Notch signaling by blocking Kuzbanian expression. Suppressing Src-JNK may restore Notch function, offering new diagnostic and therapeutic strategies for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Dysregulated Notch signaling is implicated in various cancers, exhibiting context-dependent oncogenic or tumor-suppressive roles.
- Understanding the regulatory mechanisms of Notch signaling in cancer is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the mechanisms controlling Notch signaling in cancer, specifically focusing on its role in prostate cancer.
- To elucidate the interplay between the Src-JNK pathway and Notch signaling in tumor progression.
Main Methods:
- Utilized a *Drosophila* tumor model, prostate cancer cell lines, and patient tissue samples.
- Analyzed the impact of Src-JNK pathway activity on Notch signaling components and gene expression.
- Investigated the role of Kuzbanian, a Notch S2 cleavage protease, in regulating Notch activity.
Main Results:
- Increased Src-JNK pathway activity in tumors led to the inactivation of Notch signaling.
- JNK pathway-mediated inhibition of Kuzbanian gene expression was identified as the mechanism for Notch inactivation.
- Inactive Notch accumulated in cells, impairing the transcription of tumor-suppressive target genes.
Conclusions:
- Src-JNK pathway activity serves as a potential biomarker for Notch signaling status in tumors.
- Targeting the Src-JNK pathway could restore Notch function, presenting a potential therapeutic strategy for advanced prostate cancer.
- This study provides insights into Notch signaling dysregulation and offers avenues for novel diagnostic and therapeutic approaches.
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