A conserved mechanism for JNK-mediated loss of Notch function in advanced prostate cancer

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2023-11-07 DOI:10.1126/scisignal.abo5213

Cheng-Wei Wang, Marie Clémot, Takao Hashimoto, Johnny A. Diaz, Lauren M. Goins, Andrew S. Goldstein, Raghavendra Nagaraj, Utpal Banerjee

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引用次数: 0

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.

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JNK介导的晚期前列腺癌症Notch功能缺失的保守机制。

失调的Notch信号是癌症的一个常见特征；然而，它对肿瘤起始和进展的影响是高度可变的，Notch在各种癌症中具有致癌或抑瘤功能。为了更好地了解癌症中调节Notch功能的机制，我们研究了果蝇肿瘤模型、前列腺癌衍生细胞系和晚期癌症患者组织样本中的Notch信号。我们证明，肿瘤中Src-JNK途径活性的增加使Notch信号失活，因为JNK途径介导了编码Notch S2切割蛋白酶Kuzbanian的基因的表达抑制，这对Notch活性至关重要。因此，无活性的Notch在细胞中积累，无法转录编码其靶蛋白的基因，其中许多靶蛋白具有肿瘤抑制活性。这些发现表明，肿瘤中的Src-JNK活性预测了Notch活性状态，抑制Src-JNK信号可以恢复肿瘤中的Notch功能，为晚期前列腺癌症患者提供诊断和靶向治疗的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.