A Conserved Mechanism for JNK-mediated Loss of Notch Function in Advanced Prostate Cancer

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2023 Nov 7

PMID 37934809

Authors

Cheng-Wei Wang

Marie Clemot

Takao Hashimoto

Johnny A Diaz

Lauren M Goins

Andrew S Goldstein

Raghavendra Nagaraj

Utpal Banerjee

Affiliations

Soon will be listed here.

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 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.

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