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Neutrophil Elastase Facilitates Cancer Cell Motility via Induction of Akt Signaling Pathway
Author(s) -
Ardi Veronica C.,
Deryugina Elena I.,
Quigley James P.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04626
Subject(s) - protein kinase b , cancer research , angiogenesis , tumor microenvironment , cell migration , pi3k/akt/mtor pathway , motility , chemistry , cancer cell , cell growth , neutrophil elastase , cell , cancer , signal transduction , microbiology and biotechnology , biology , immunology , medicine , inflammation , biochemistry , tumor cells
Cancer cells create a microenvironment favoring growth of the primary tumor and cancer dissemination. We and others have demonstrated that immune cells recruited to a primary tumor actively contribute to pro‐tumorigenic and pro‐metastatic conditions. Neutrophils, one of the first inflammatory leukocytes infiltrating a developing tumor, facilitate intratumoral angiogenesis and tumor cell dissemination via newly formed blood vessels. Upon arrival to the site of primary tumor, the recruited neutrophils release their potent enzymes, including neutrophil MMP‐9, a structurally unique metalloproteinase strongly inducing angiogenesis. Herein, we demonstrate that a neutrophil‐derived serine protease, neutrophil elastase (NE), enhances cancer cell motility, which is essential for efficient cancer cell dissemination from primary tumors to secondary sites. We have shown that the treatment of tumor cells with purified NE significantly increased their migration in a chemotactic Transwell assay. Our data show significant (by 2‐fold) increase in migration rates of NE‐treated over non‐treated control for both epidermoid HEp3 and prostate PC3 carcinoma cells. We found no direct effect of NE treatment on cell proliferation, thus excluding cell division from the causes of NE‐mediated increase in rates of cell migration. However, we found that NE treatment induced activation of Akt, a protein kinase that regulates many important cell functions. We have demonstrated that NE‐mediated activation of Akt was sensitive to the specific NE inhibitor, α1PI, implicating the catalytic activity of NE in the enhancement of cell migration. Furthermore, NE‐induced cell migration was completely abrogated if tumor cells were pre‐treated with inhibitors of Akt signaling, Dasatinib and Wortmannin, before NE treatment. Together, our findings indicate that neutrophil‐specific protease, NE, is a potent inducer of tumor cell migration, and that Akt‐activation signaling constitutes an essential mechanism for NE‐enhancing effects on tumor cell migration.