Pyruvate dehydrogenase kinase 4-mediated metabolic reprogramming is involved in rituximab resistance in diffuse large B-cell lymphoma by affecting the expression of MS4A1/CD20

Cancer Sci. 2021 Sep;112(9):3585-3597. doi: 10.1111/cas.15055. Epub 2021 Jul 28.


Diffuse large B cell lymphoma (DLBCL) heterogeneity promotes recurrence and anti-CD20-based therapeutic resistance. Previous studies have shown that downregulation of MS4A1/CD20 expression after chemoimmunotherapy with rituximab leads to rituximab resistance. However, the mechanisms of CD20 loss remain unknown. We identified that pyruvate dehydrogenase kinase 4 (PDK4) is markedly elevated in DLBCL cells derived from both patients and cell lines with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) resistance. We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression. Collectively, this is the first study showing that targeting PDK4 has the potential to overcome rituximab resistance in DLBCL.

Keywords: MS4A1/CD20; PDK4; diffuse large B-cell lymphoma; metabolic reprogramming; rituximab.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antigens, CD20 / metabolism*
  • Antineoplastic Agents, Immunological / administration & dosage*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cellular Reprogramming / genetics*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Glycoproteins / metabolism*
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Male
  • Mice
  • Middle Aged
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism*
  • Rituximab / administration & dosage*
  • Signal Transduction / genetics*
  • Transfection
  • Treatment Outcome
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays
  • Young Adult


  • Antigens, CD20
  • Antineoplastic Agents, Immunological
  • Glycoproteins
  • MS4A1 protein, human
  • PDK4 protein, human
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Rituximab