Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China.
Department of Hematology, Affiliated Hospital of Guilin Medical University, Guilin, China.
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.
弥漫性大 B 细胞淋巴瘤（DLBCL）的异质性促进了复发和抗 CD20 为基础的治疗耐药性。先前的研究表明，利妥昔单抗联合化疗后 MS4A1/CD20 表达的下调导致利妥昔单抗耐药。然而，CD20 丢失的机制仍不清楚。我们发现，丙酮酸脱氢酶激酶 4（PDK4）在来自患者和具有 R-CHOP（利妥昔单抗联合环磷酰胺、多柔比星、长春新碱和泼尼松）耐药的细胞系的 DLBCL 细胞中明显升高。我们发现，PDK4 在 DLBCL 细胞中的过表达导致细胞增殖和对利妥昔单抗的耐药性，无论是在体外还是体内。此外，PDK4 表达的缺失或 PDK4 抑制剂二氯乙酸的治疗能够显著增加 DLBCL 细胞中利妥昔单抗诱导的细胞凋亡。进一步的研究表明，PDK4 介导了一种代谢转变，即主要的能量来源从氧化磷酸化转变为糖酵解，代谢变化可能在利妥昔单抗耐药中发挥重要作用。重要的是，通过在 DLBCL 细胞中敲低或过表达 PDK4，我们表明 PDK4 对 MS4A1/CD20 的表达具有负调节作用。总的来说，这是第一项表明靶向 PDK4 有可能克服 DLBCL 中的利妥昔单抗耐药性的研究。
