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Exosome-Transmitted PSMA3 and PSMA3-AS1 Promote Proteasome Inhibitor Resistance in Multiple Myeloma

Hongxia Xu1,2, Huiying Han1, Sha Song1

  • 1Department of Cell Biology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 6, 2019
PubMed
Abstract

Insights

Exosomes carrying PSMA3 and PSMA3-AS1 from mesenchymal stem cells confer proteasome inhibitor resistance in multiple myeloma. These exosomal RNAs may serve as therapeutic targets and prognostic predictors for multiple myeloma patients.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • The bone marrow microenvironment influences multiple myeloma (MM) cell behavior.
  • Proteasome inhibitors (PI) are a cornerstone of MM treatment, but resistance remains a challenge.

Purpose of the Study:

  • To investigate the role of exosomal RNAs in mediating PI resistance in MM.
  • To identify specific exosomal RNAs and their mechanisms of action in promoting PI resistance.

Main Methods:

  • Exosomes were isolated from mesenchymal stem cells (MSCs) and characterized.
  • Co-culture experiments assessed exosomal RNA transfer from MSCs to MM cells.
  • In vivo studies evaluated the effect of siPSMA3-AS1 on carfilzomib sensitivity in xenograft models.
  • Circulating exosomal PSMA3 and PSMA3-AS1 levels were analyzed in MM patients for prognostic significance using Cox regression and Kaplan-Meier analysis.

Main Results:

  • Exosomes from MSCs containing PSMA3 and PSMA3-AS1 were transferred to MM cells, inducing PI resistance.
  • PSMA3-AS1 formed an RNA duplex with pre-PSMA3, enhancing PSMA3 expression and stability.
  • Administration of siPSMA3-AS1 increased carfilzomib sensitivity in vivo.
  • Elevated levels of circulating exosomal PSMA3 and PSMA3-AS1 correlated significantly with progression-free survival and overall survival in MM patients.

Conclusions:

  • Exosomal PSMA3 and PSMA3-AS1 play a critical role in mediating PI resistance in MM by transferring from MSCs via a novel signaling pathway.
  • These exosomal RNAs represent potential therapeutic targets for overcoming PI resistance in MM.
  • Circulating exosomal PSMA3 and PSMA3-AS1 may serve as valuable prognostic biomarkers for clinical outcomes in MM.

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