Profilin 1 induces drug resistance by downregulating CD138 expression via autophagy in multiple myeloma

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Multiple myeloma (MM) treatment often involves bortezomib, but drug resistance is a significant clinical challenge.
• Profilin 1 (PFN1) is implicated in promoting autophagy and bortezomib resistance in MM, yet the underlying mechanisms remain unclear.
• CD138, a key marker in MM, is also being investigated for its role in drug resistance.

Purpose of the Study:

• To elucidate the molecular mechanisms by which PFN1 induces bortezomib resistance in multiple myeloma.
• To investigate the interplay between PFN1, CD138 expression, and autophagy in the context of bortezomib resistance.
• To identify potential therapeutic targets for overcoming PFN1-mediated drug resistance in MM.

Main Methods:

• Immunohistochemistry to detect CD138 and PFN1 in patient bone marrow samples.
• Analysis of Gene Expression Omnibus (GEO) data to correlate CD138, PFN1, and autophagy.
• Western blot, immunofluorescence, and flow cytometry to evaluate protein expression in MM cell lines.
• Generation of PFN1-overexpressing and -knockdown MM cell lines.
• Functional assays including clonogenic, apoptosis, and CCK-8 assays to assess drug resistance.

Main Results:

• PFN1 overexpression or PFN1-induced autophagy led to downregulated CD138 expression in MM cells.
• CD138 expression was found to be associated with PFN1 and autophagy in MM.
• Inhibition of autophagy or CD138 overexpression reversed bortezomib resistance in PFN1-overexpressing MM cells.
• Ubiquitinated CD138 was detected in PFN1-manipulated MM cells.

Conclusions:

• CD138 plays a crucial role in mediating bortezomib resistance in multiple myeloma.
• PFN1-induced downregulation of CD138, potentially through autophagy, contributes to drug resistance.
• Targeting PFN1, CD138, or autophagic pathways presents a promising therapeutic strategy against PFN1-induced bortezomib resistance in MM.