Cancer cells use multiple mechanisms to evade the effects of glutamine metabolism inhibitors. The pathways that govern responses to alterations in glutamine availability within the tumor may represent therapeutic targets for combinatorial strategies with these inhibitors. Here, we showed that targeting glutamine utilization stimulated Yes-associated protein (YAP) signaling in cancer cells by reducing cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent phosphorylation of large tumor suppressor (LATS). Elevated YAP activation induced extracellular matrix (ECM) deposition by increasing secretion of connective tissue growth factor (CTGF) that promoted production of fibronectin and collagen by surrounding fibroblasts. Consequently, inhibiting YAP synergized with inhibition of glutamine utilization to effectively suppress tumor growth in vivo, along with a concurrent decrease in ECM deposition. Blocking ECM remodeling also augmented the tumor suppressive effects of the glutamine utilization inhibitor. Collectively, these data reveal mechanisms by which targeting glutamine utilization increases ECM accumulation and identify potential strategies to reduce ECM levels and increase the efficacy of glutamine metabolism inhibitors.

中文翻译：

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靶向 YAP 活性和谷氨酰胺代谢通过阻止细胞外基质积累来协同抑制肿瘤进展


癌细胞使用多种机制来逃避谷氨酰胺代谢抑制剂的作用。控制对肿瘤内谷氨酰胺可用性变化的反应的通路可能代表与这些抑制剂组合策略的治疗靶点。在这里，我们表明靶向谷氨酰胺利用通过减少大型肿瘤抑制基因 （LATS） 的环磷酸腺苷 （cAMP）/蛋白激酶 A （PKA） 依赖性磷酸化来刺激癌细胞中的 Yes 相关蛋白 （YAP） 信号传导。YAP 激活升高通过增加结缔组织生长因子 （CTGF） 的分泌诱导细胞外基质 （ECM） 沉积，从而促进周围成纤维细胞产生纤连蛋白和胶原蛋白。因此，抑制 YAP 与抑制谷氨酰胺利用协同作用，有效抑制体内肿瘤生长，同时减少 ECM 沉积。阻断 ECM 重塑还增强了谷氨酰胺利用抑制剂的肿瘤抑制作用。总的来说，这些数据揭示了靶向谷氨酰胺利用增加 ECM 积累的机制，并确定了降低 ECM 水平和提高谷氨酰胺代谢抑制剂疗效的潜在策略。