Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland.
Nat Commun. 2016 Dec 12;7:13719. doi: 10.1038/ncomms13719.
Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients.
NOTCH 信号的激活与晚期前列腺癌和前列腺癌患者的治疗耐药有关。然而，驱动前列腺癌中 NOTCH 激活的机制仍然难以捉摸。此外，缺乏 NOTCH 抑制剂在前列腺癌中的临床前疗效证据。在这里，我们提供的证据表明，PTEN 缺失会在上皮性肿瘤中上调 ADAM17 的表达，从而激活 NOTCH 信号。使用前列腺条件性敲除 Pten 和 Notch1 以及在 Pten 缺失前列腺条件性小鼠模型中进行的临床前试验，我们证明 Pten 缺失的前列腺肿瘤依赖于 NOTCH 信号。重要的是，我们发现 γ-分泌酶的药理学抑制通过触发细胞衰老促进 Pten 缺失和 Pten/Trp53 缺失的前列腺肿瘤的生长停滞。总之，我们的研究结果描述了一个新的促肿瘤发生网络，将 PTEN 缺失与 ADAM17 和 NOTCH 信号联系起来，从而为晚期前列腺癌患者使用 γ-分泌酶抑制剂提供了合理依据。
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