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-XL) 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.

中文翻译：

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基质细胞蛋白激酶 C-β 抑制可增强 B 细胞恶性肿瘤的化疗敏感性并克服耐药性。


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，该通路有助于恶性 B 细胞的耐药性。我们发现，来自骨髓基质细胞的蛋白激酶 C (PKC)-β 依赖性信号显着降低了细胞毒性疗法的功效。相反，小分子 PKC-β 抑制剂拮抗基质细胞的促生存信号，并使肿瘤细胞对靶向和非靶向化疗敏感，从而增强细胞毒性并延长体内存活时间。从机制上讲，基质 PKC-β 控制粘附蛋白和基质蛋白的表达，这是激活磷酸肌醇 3 激酶 (PI3K) 和细胞外信号调节激酶 (ERK) 介导的 B 细胞淋巴瘤特大 (BCL-XL) 稳定所需的蛋白。 ）在肿瘤细胞中。基质介导的耐药性的核心是转录因子 EB 的 PKC-β 依赖性激活，调节溶酶体生物发生和质膜完整性。通过直接抑制 PKC-β 实现的基质导向疗法可增强许多抗白血病疗法的有效性。