Wellcome Trust/MRC Cambridge Stem Cell Institute and Department of Haematology, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AH, UK.
Department of Biochemistry and University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT 05405, USA.
Sci Transl Med. 2020 Jan 15;12(526). doi: 10.1126/scitranslmed.aax9340.
Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell-autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)-β-dependent signals from bone marrow-derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal-regulated kinase (ERK)-mediated stabilization of B cell lymphoma-extra large (BCL-X) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-β-dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-β, enhance the effectiveness of many antileukemic therapies.
克服耐药性仍然是治愈急性和慢性 B 细胞恶性肿瘤患者的关键挑战。在这里，我们描述了一种基质细胞自主信号通路，它有助于恶性 B 细胞的耐药性。我们表明，来自骨髓来源的基质细胞的蛋白激酶 C（PKC）-β依赖性信号显著降低细胞毒性治疗的效果。相反，小分子 PKC-β 抑制剂拮抗来自基质细胞的生存信号，并使肿瘤细胞对靶向和非靶向化疗敏感，导致体内细胞毒性增强和存活时间延长。在机制上，基质 PKC-β控制着黏附和基质蛋白的表达，这些蛋白对于磷酸肌醇 3-激酶（PI3K）的激活和细胞外信号调节激酶（ERK）介导的 B 细胞淋巴瘤特大（BCL-X）在肿瘤细胞中的稳定是必需的。以转录因子 EB 的 PKC-β依赖性激活为中心，调节溶酶体生物发生和质膜完整性。通过直接抑制 PKC-β 实现的基质定向治疗增强了许多抗白血病治疗的效果。
