Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Sci Signal. 2023 Nov 7;16(810):eabo5213. doi: 10.1126/scisignal.abo5213.
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.
Notch 信号通路失调是癌症的一个常见特征；然而，其对肿瘤起始和进展的影响具有高度可变性，Notch 在各种癌症中具有致癌或肿瘤抑制功能。为了更好地理解调节癌症中 Notch 功能的机制，我们研究了肿瘤模型、前列腺癌细胞系和晚期前列腺癌患者组织样本中的 Notch 信号通路。我们证明，肿瘤中Src-JNK 通路的活性增加会使 Notch 信号失活，因为 JNK 通路介导了 Notch S2 切割蛋白酶编码基因 Kuzbanian 的表达抑制，而 Kuzbanian 对于 Notch 活性至关重要。因此，失活的 Notch 在细胞中积累，而无法转录其靶蛋白编码基因，其中许多基因具有肿瘤抑制活性。这些发现表明，肿瘤中的 Src-JNK 活性可预测 Notch 活性状态，抑制 Src-JNK 信号通路可能恢复肿瘤中的 Notch 功能，为晚期前列腺癌患者的一部分提供诊断和靶向治疗的机会。
