PMEPA1 Binds NEDD4L to Inhibit the Malignant Progression of Multiple Myeloma by Inactivating Wnt/β-Catenin Signaling

Area of Science:

• Hematological Malignancies
• Molecular Biology
• Cancer Signaling Pathways

Background:

• Multiple myeloma (MM) is an incurable hematological malignancy with increasing prevalence.
• The role of Prostate transmembrane androgen inducible protein 1 (PMEPA1) in MM pathogenesis is not fully understood, despite its association with patient survival.
• Understanding PMEPA1's interaction with other proteins like neural precursor cell-expressed developmentally downregulated gene 4L (NEDD4L) is crucial for elucidating its function in MM.

Purpose of the Study:

• To investigate the expression levels and functional roles of PMEPA1 and NEDD4L in multiple myeloma cells.
• To elucidate the molecular mechanisms by which PMEPA1 influences MM cell proliferation, cell cycle distribution, and apoptosis.
• To determine the interaction between PMEPA1 and NEDD4L and its impact on the Wnt/β-catenin signaling pathway in MM.

Main Methods:

• Examined PMEPA1 and NEDD4L expression in MM cells.
• Utilized cell culture (RPMI-8226) with PMEPA1 overexpression and/or NEDD4L knockdown to assess proliferation (CCK-8, EDU staining), cell cycle, and apoptosis (flow cytometry).
• Predicted and validated PMEPA1-NEDD4L binding (BioGrid, HDOCK, co-immunoprecipitation), and analyzed protein levels (immunoblotting) related to proliferation, apoptosis, and Wnt/β-catenin signaling. Investigated the effect of Wnt/β-catenin activator LiCl.

Main Results:

• PMEPA1 and NEDD4L were found to be expressed at low levels in MM cells.
• PMEPA1 upregulation suppressed proliferation, induced cell cycle arrest, and promoted apoptosis in MM cells.
• PMEPA1 directly bound to NEDD4L, increasing its expression and mediating its anti-proliferative and pro-apoptotic effects, while downregulating Wnt/β-catenin signaling components (β-catenin, c-Myc, cyclin D1). NEDD4L knockdown abrogated these effects.

Conclusions:

• PMEPA1 inhibits multiple myeloma progression by interacting with NEDD4L to suppress the Wnt/β-catenin signaling pathway.
• The PMEPA1-NEDD4L axis represents a potential therapeutic strategy for targeting MM.
• Further research into this pathway could lead to novel treatments for this hematological malignancy.