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<p>Multiple myeloma (MM), a plasma cell-derived malignant hematological disease, is often treated with bortezomib, a highly effective first-generation proteasome inhibitor. However, resistance to bortezomib is a common occurrence. Profilin 1 (PFN1), a cytoskeleton-related gene known to promote autophagy in MM, induces this resistance to bortezomib, but it is unclear why. The aim of this study was to uncover the molecular mechanisms involved in bortezomib resistance, considering not only PFN1, but also CD138, a transmembrane proteoglycan that is a hallmark of plasma and MM cells. We detected CD138 and PFN1 in the bone marrow of patients with MM immunohistochemically. We also studied the Gene Expression Omnibus (GEO) data and found that CD138 was associated with PFN1 and autophagy. We then evaluated their expression in an MM cell line via western blot analysis, immunofluorescence assay, and flow cytometry; constructed PFN1-overexpressing and -knockdown cell lines; and detected ubiquitinated CD138 in the cells of both cell lines. Overexpression of PFN1 or PFN1-induced autophagy downregulated CD138 expression. Owing to the stemness and resistance of CD138<sup>−</sup> MM cells, inhibition of autophagy or CD138 overexpression reversed the resistance of PFN1-overexpressing MM cells to bortezomib, as indicated in our clonogenic, apoptosis, and CCK-8 assays. These results indicated that CD138 plays an important role in the resistance of MM cells to bortezomib. Targeting PFN1, CD138, or autophagic pathways may provide a promising therapeutic strategy for overcoming PFN1-induced drug resistance in MM.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月8日

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  • Ya Wang,
  • ZiYu Dai,
  • Shengying Xiao,
  • Furen Zeng,
  • YiChen Lu

摘要

Multiple myeloma (MM), a plasma cell-derived malignant hematological disease, is often treated with bortezomib, a highly effective first-generation proteasome inhibitor. However, resistance to bortezomib is a common occurrence. Profilin 1 (PFN1), a cytoskeleton-related gene known to promote autophagy in MM, induces this resistance to bortezomib, but it is unclear why. The aim of this study was to uncover the molecular mechanisms involved in bortezomib resistance, considering not only PFN1, but also CD138, a transmembrane proteoglycan that is a hallmark of plasma and MM cells. We detected CD138 and PFN1 in the bone marrow of patients with MM immunohistochemically. We also studied the Gene Expression Omnibus (GEO) data and found that CD138 was associated with PFN1 and autophagy. We then evaluated their expression in an MM cell line via western blot analysis, immunofluorescence assay, and flow cytometry; constructed PFN1-overexpressing and -knockdown cell lines; and detected ubiquitinated CD138 in the cells of both cell lines. Overexpression of PFN1 or PFN1-induced autophagy downregulated CD138 expression. Owing to the stemness and resistance of CD138− MM cells, inhibition of autophagy or CD138 overexpression reversed the resistance of PFN1-overexpressing MM cells to bortezomib, as indicated in our clonogenic, apoptosis, and CCK-8 assays. These results indicated that CD138 plays an important role in the resistance of MM cells to bortezomib. Targeting PFN1, CD138, or autophagic pathways may provide a promising therapeutic strategy for overcoming PFN1-induced drug resistance in MM.