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Connexin 43 gap junction affects survival and drug resistance of multiple myeloma side population cells

Z Wang1, J X Fu2, X H Zhang1

  • 1Department of Hematology, No.2 Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.

Journal of Physiology and Pharmacology : an Official Journal of the Polish Physiological Society
|September 3, 2023
PubMed

Insights

Drug resistance in multiple myeloma (MM) involves side population (SP) cells. Connexin 43 (Cx43)-mediated gap junction intercellular communication (GJ-IC) between MM and bone marrow mesenchymal stem cells (BMSCs) promotes MM survival and drug resistance.

Area of Science:

  • Hematology
  • Cancer Biology
  • Cellular Communication

Background:

  • Drug resistance is a significant hurdle in multiple myeloma (MM) treatment.
  • Side population (SP) cells are implicated in MM drug resistance.
  • The role of connexin 43 (Cx43)-mediated gap junction intercellular communication (GJ-IC) in MM cells is not well understood.

Purpose of the Study:

  • To investigate the function of Cx43-mediated GJ-IC in MM cells.
  • To determine the impact of bone marrow mesenchymal stem cells (BMSCs) on MM SP cell behavior and drug resistance.
  • To elucidate the mechanisms underlying MM drug resistance involving GJ-IC.

Main Methods:

  • Isolation and culture of BMSCs from various sources.
  • Separation of MM RPMI 8226 SP cells using flow cytometry.
  • Detection of Cx43 mRNA and protein expression via real-time RT-PCR and Western blot.
  • Assessment of BMSC effects on SP cell cycle, proliferation, stem cell gene expression, and drug resistance, with and without the GJ-IC inhibitor 18α-glycyrrhetinic acid (18αGA).

Main Results:

  • MM cells express Cx43 and contain a substantial population of SP cells.
  • SP cells exhibited increased survival and proliferation compared to RPMI 8226 cells; 18αGA reduced these effects.
  • MM cells showed reduced sensitivity to dexamethasone and bortezomib when co-cultured with BMSCs, an effect partially reversed by 18αGA.

Conclusions:

  • GJ-IC between BMSCs and MM cells is a key regulatory mechanism for MM cell survival and proliferation.
  • GJ-IC contributes to MM drug resistance.
  • Targeting GJ-IC may offer a therapeutic strategy to overcome drug resistance in multiple myeloma.

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