Xiao Zhiguang, Hammes Stephen R
Department of Medicine, University of Rochester Medical Center, Rochester, NY 14620, USA.
iScience. 2021 Oct 14;24(11):103270. doi: 10.1016/j.isci.2021.103270. eCollection 2021 Nov 19.
Neutrophil elastase (NE) promotes multiple stages of tumorigenesis. However, little is known regarding the molecular mechanisms underlying its stimulatory role. This study shows that NE triggers dose-dependent ERK signaling and cell migration in a panel of prostate cell lines representing the spectrum of prostate cell malignancy. All cell lines tested internalize NE; however, NE endocytosis is not required for ERK activation. Instead, NE acts extracellularly by stimulating the release of amphiregulin to initiate EGFR-dependent signaling. Inhibiting amphiregulin's biological activity with neutralizing antibodies, as well as gene silencing of amphiregulin or EGFR, attenuates NE-induced migration in normal and benign prostatic cells. Alternatively, in prostate cancer cells, knockdown of receptor tyrosine kinase AXL, but not EGFR, impairs both basal and NE-stimulated migration. When prostate cells progress to malignancy, the switch from EGFR-to AXL-dependence in NE-mediated migration implies the potential combined application of EGFR and AXL targeted therapy in prostate cancer treatment.
中性粒细胞弹性蛋白酶（NE）促进肿瘤发生的多个阶段。然而，关于其刺激作用背后的分子机制却知之甚少。本研究表明，NE在一组代表前列腺细胞恶性程度谱的前列腺细胞系中触发剂量依赖性的ERK信号传导和细胞迁移。所有测试的细胞系均内化NE；然而，ERK激活并不需要NE内吞作用。相反，NE通过刺激双调蛋白的释放来启动EGFR依赖性信号传导，从而在细胞外发挥作用。用中和抗体抑制双调蛋白的生物学活性，以及双调蛋白或EGFR的基因沉默，均可减弱NE诱导的正常和良性前列腺细胞的迁移。另外，在前列腺癌细胞中，受体酪氨酸激酶AXL的敲低而非EGFR的敲低，会损害基础迁移和NE刺激的迁移。当前列腺细胞发展为恶性时，NE介导的迁移中从EGFR依赖性向AXL依赖性的转变意味着EGFR和AXL靶向治疗在前列腺癌治疗中的潜在联合应用。
