Notch 信号传导失调是癌症的一个常见特征。然而，它对肿瘤发生和进展的影响差异很大，Notch 在各种癌症中具有致癌或肿瘤抑制功能。为了更好地了解癌症中Notch功能的调节机制，我们研究了果蝇肿瘤模型、前列腺癌衍生细胞系和晚期前列腺癌患者的组织样本中的Notch信号传导。我们证明，肿瘤中 Src-JNK 通路活性的增加会使 Notch 信号失活，因为 JNK 通路介导的对编码 Notch S2 裂解蛋白酶 Kuzbanian 的基因表达的抑制，该基因对 Notch 活性至关重要。因此，失活的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 活性可以预测 Notch 活性状态，而抑制 Src-JNK 信号传导可以恢复肿瘤中的 Notch 功能，从而为部分晚期前列腺癌患者提供诊断和靶向治疗的机会。

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.