Aberrant ENPP2 expression promotes tumor progression in multiple myeloma

Abstract

Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) disease progression remains unclear. Here, we demonstrated that CD138+ cells isolated from MM patients presented with higher expression of ENPP2 compared with CD138- cells. Treatment of MM cells with IL-6 resulted in ENPP2 upregulation. ENPP2 overexpression promoted proliferation, inhibited apoptosis, increased lysophosphatidic acid (LPA) generation, and upregulated osteoclastogenesis mediator expression in MM cells. In contrast, ENPP2 inhibition induced apoptosis, suppressed proliferation and survival, decreased LPA generation and downregulated osteoclastogenesis mediator expression. In an MM xenograft mouse model, ENPP2 knockdown significantly reduced MM tumor burden by inhibiting cell proliferation and inducing apoptosis. Furthermore, ENPP2 knockdown decreased the levels of LPA, osteoclastogenesis mediators in sera of mice with MM. Our findings revealed the tumor-promoting role of ENPP2 in MM, thus providing new molecular evidence for targeting the ENPP2-LPA axis in MM therapy.

Keywords:

• ENPP2
• multiple myeloma
• disease progression
• LPA
• tumor

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Key Research and Development Program of China under Grant [2017YFA0105303]; China Postdoctoral Science Foundation under Grant [2020M682128] and National Major Scientific and Technological Special Project for “Significant New Drug Development” under Grant [2018ZX09733-003].