Involvement of the arachidonic acid cytochrome P450 epoxygenase pathway in the proliferation and invasion of human multiple myeloma cells.

Jing Shao,Qiubai Li,Guolin Yuan,Zhichao Chen,Hongxiang Wang

doi:10.7717/peerj.1925

Abstract

Cytochrome P450 (CYP) epoxygenases and the metabolites epoxyeicosatrienoic acids (EETs) exert multiple biological effects in various malignancies. We have previously found EETs to be secreted by multiple myeloma (MM) cells and to be involved in MM angiogenesis, but the role of the arachidonic acid cytochrome P450 epoxygenase pathway in the proliferation and mobility of MM cells remains unknown. In the present study, we found that MM cell lines generated detectable levels of 11,12-EET/14,15-EET and that increased levels of EETs were found in the serum of MM patients compared to healthy donors. The addition of exogenous EETs induced significantly enhanced proliferation of MM cells, whereas 17-octadecynoic acid (17-ODYA), an inhibitor of the CYP epoxygenase pathway, inhibited the viability and proliferation of MM cells. Moreover, this inhibitory effect could be successfully reversed by exogenous EETs. 17-ODYA also inhibited the motility of MM cells in a time-dependent manner, with a reduction of the gelatinolytic activity and protein expression of the matrix metalloproteinases (MMP)-2 and MMP-9. These results suggest the CYP epoxygenase pathway to be involved in the proliferation and invasion of MM cells, for which 17-ODYA could be a promising therapeutic drug.

Highlights

It is well known that arachidonic acid (AA) is converted to eicosanoid mediators by the cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP) epoxygenase pathways to generate hundreds of metabolites that have different biological activities and contribute to the pathogenesis of numerous diseases
We previously demonstrated that MM cells secrete epoxyeicosatrienoic acids (EETs) into the supernatant and that the CYP epoxygenase pathway participates in the MM cell-induced angiogenesis, which can be inhibited by 17-octadecynoic acid (17-ODYA), an inhibitor of CYP epoxygenase pathway (Shao et al, 2011)
These results indicate that CYP epoxygenase-derived EETs promote the viability of MM cells and that CYP epoxygenases may play an important role in the proliferation of multiple myeloma

Summary

Introduction

It is well known that arachidonic acid (AA) is converted to eicosanoid mediators by the cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP) epoxygenase pathways to generate hundreds of metabolites that have different biological activities and contribute to the pathogenesis of numerous diseases. Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by the accumulation. How to cite this article Shao et al (2016), Involvement of the arachidonic acid cytochrome P450 epoxygenase pathway in the proliferation and invasion of human multiple myeloma cells. AA metabolism pathways are involved in the pathogenesis of multiple myeloma (MM). The role of the cytochrome P450 epoxygenase pathway in the disease progression of MM remains poorly understood

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