Cathepsin G-induced malignant progression of MCF-7 cells involves suppression of PAF signaling through induced expression of PAFAH1B2

Kazunari Tanigawa, Mitsuo Kiriya, Yasuhiro Hayashi, Yoshiaki Shinden, Yuko Kijima, Shoji Natsugoe, Takahiro Sumimoto, Riyo Morimoto-Kamata, Satoru Yui, Kotaro Hama, Kazuaki Yokoyama, Yasuhiro Nakamura, Koichi Suzuki, Hisao Nojiri, Keizo Inoue, Ken Karasawa

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Breast cancer is primarily classified into ductal and lobular types, as well as into noninvasive and invasive cancer. Invasive cancer involves lymphatic and hematogenous metastasis. In breast cancer patients with distant metastases, a neutrophil-derived serine protease; cathepsin G (Cat G), is highly expressed in breast cancer cells. Cat G induces cell migration and multicellular aggregation of MCF-7 human breast cancer cells; however, the mechanism is not clear. Recently, platelet-activating factor (PAF)-acetylhydrolase (PAF-AH), the enzyme responsible for PAF degradation, was reported to be overexpressed in some tumor types, including pancreatic and breast cancers. In this study, we investigated whether PAF-AH is involved in Cat G-induced aggregation and migration of MCF-7 cells. We first showed that Cat G increased PAF-AH activity and elevated PAFAH1B2 expression in MCF-7 cells. The elevated expression of PAFAH1B2 was also observed in human breast cancer tissue specimens by immunohistochemical analysis. Furthermore, knockdown of PAFAH1B2 in MCF-7 cells suppressed the cell migration and aggregation induced by low concentrations, but not high concentrations, of Cat G. Carbamoyl PAF (cPAF), a nonhydrolyzable PAF analog, completely suppressed Cat G-induced migration of MCF-7 cells. In addition, PAF receptor (PAFR) inhibition induced cell migration of MCF-7 cells even in the absence of Cat G, suggesting that Cat G suppresses the activation of PAFR through enhanced PAF degradation due to elevated expression of PAFAH1B2 and thereby induces malignant phenotypes in MCF-7 cells. Our findings may lead to a novel therapeutic modality for treating breast cancer by modulating the activity of Cat G/PAF signaling.

Original languageEnglish
Article number159164
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1867
Issue number8
DOIs
Publication statusPublished - 08-2022

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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