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AXL cooperates with EGFR to mediate neutrophil elastase-induced migration of prostate cancer cells

ABSTRACT: Summary 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. Graphical abstract Highlights • NE triggers the release of AREG to activate EGFR/ERK signaling in prostate cells• AREG-EGFR axis is critical in NE-induced migration of nonmalignant prostate cells• NE promotes prostate cancer cell migration via AXL rather than EGFR• Accessibility of NE in prostate cells may be associated with cell malignancy Cancer; Cell biology

SUBMITTER: Xiao Z

PROVIDER: S-EPMC8567381 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo.

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