Department of Pharmacology, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, and University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
J Biol Chem. 2012 Aug 10;287(33):27863-75. doi: 10.1074/jbc.M112.384685. Epub 2012 Jun 8.
Acidosis arises in solid and lymphoid malignancies secondary to altered nutrient supply and utilization. Tumor acidosis correlates with therapeutic resistance, although the mechanism behind this effect is not fully understood. Here we show that incubation of lymphoma cell lines in acidic conditions (pH 6.5) blocks apoptosis induced by multiple cytotoxic metabolic stresses, including deprivation of glucose or glutamine and treatment with dexamethasone. We sought to examine the role of the Bcl-2 family of apoptosis regulators in this process. Interestingly, we found that acidic culture causes elevation of both Bcl-2 and Bcl-xL, while also attenuating glutamine starvation-induced elevation of p53-up-regulated modulator of apoptosis (PUMA) and Bim. We confirmed with knockdown studies that these shifts direct survival decisions during starvation and acidosis. Importantly, the promotion of a high anti- to pro-apoptotic Bcl-2 family member ratio by acidosis renders cells exquisitely sensitive to the Bcl-2/Bcl-xL antagonist ABT-737, suggesting that acidosis causes Bcl-2 family dependence. This dependence appears to be mediated, in part, by the acid-sensing G protein-coupled receptor, GPR65, via a MEK/ERK pathway.
酸中毒在实体瘤和淋巴系统恶性肿瘤中继发于营养供应和利用的改变。肿瘤酸中毒与治疗抵抗相关，尽管其背后的机制尚不完全清楚。在这里，我们发现将淋巴瘤细胞系在酸性条件（pH6.5）下孵育会阻止多种细胞毒性代谢应激诱导的细胞凋亡，包括葡萄糖或谷氨酰胺剥夺和地塞米松治疗。我们试图研究凋亡调节蛋白 Bcl-2 家族在这个过程中的作用。有趣的是，我们发现酸性培养会导致 Bcl-2 和 Bcl-xL 的升高，同时也减弱了谷氨酰胺饥饿诱导的 p53 上调凋亡调节因子（PUMA）和 Bim 的升高。通过敲低研究证实，这些变化直接影响饥饿和酸中毒时的存活决策。重要的是，酸中毒通过促进高的抗凋亡到促凋亡 Bcl-2 家族成员比例，使细胞对 Bcl-2/Bcl-xL 拮抗剂 ABT-737 变得极其敏感，表明酸中毒引起 Bcl-2 家族依赖性。这种依赖性部分是由酸感应 G 蛋白偶联受体 GPR65 通过 MEK/ERK 途径介导的。
