Mitochondria regulate the unfolded protein response leading to cancer cell survival under glucose deprivation conditions. Homo sapiens

Cancer cells consume large amounts of glucose because of their specific metabolic pathway. However, cancer cells exist in tumor tissue where glucose is insufficient. To survive, cancer cells likely have the mechanism to elude their glucose addiction. Here we show that functional mitochondria are essential if cancer cells are to avoid glucose addiction. Cancer cells with dysfunctional mitochondria, such as mitochondrial DNA-deficient rho0 cells and electron transport chain blocker-treated cells, were highly sensitive to glucose deprivation. Our data demonstrated that this sensitization was caused by failure of the unfolded protein response (UPR), an adaptive response mediated by the endoplasmic reticulum (ER). This study suggests a link between mitochondria and the ER during the UPR under glucose deprivation conditions and that mitochondria govern cell fate, not only through ATP production and apoptosis regulation but also through modulating the UPR for cell survival. Overall design: Human cancer cell lines (HT-1080, HT-29, and mtDNA-deficient cells derived from these cell lines) were selected for RNA extraction and hybridization on Affymetrix microarrays. We examined the unfolded protein response (UPR), an adaptive response mediated by the endoplasmic reticulum (ER), of cancer cells under stress conditions. Abbreviations List: AA, antimycin A; Bu, buformin; Met, metformin; Phen, phenformin; Rot, rotenone; VST, versipelostatin; TM, tunicamycin; 2DG, 2-deoxyglucose; GS, glucose starvation. Capital S (_S) indicates the supernatant of sample including floating cells.

癌细胞因其特异性代谢通路，会大量摄取葡萄糖。然而，癌细胞定植的实体瘤组织内葡萄糖供应匮乏，为维持存活，癌细胞大概率具备规避葡萄糖成瘾性的机制。本研究证实，功能完整的线粒体是癌细胞规避葡萄糖成瘾性的必要条件。线粒体功能异常的癌细胞（例如线粒体DNA缺陷型rho0细胞（rho0 cells）、经电子传递链抑制剂处理的细胞）对葡萄糖剥夺呈现高度敏感性。本研究数据表明，该敏感性增强源于未折叠蛋白反应（unfolded protein response, UPR）的功能失调——未折叠蛋白反应是由内质网（endoplasmic reticulum, ER）介导的适应性应答通路。本研究揭示了葡萄糖剥夺条件下，线粒体与内质网在未折叠蛋白反应过程中的关联，并证实线粒体不仅通过ATP生成与凋亡调控来决定细胞命运，还可通过调节未折叠蛋白反应以维持细胞存活。
实验设计概述：选取人类癌细胞系（HT-1080、HT-29以及源自这两种细胞系的线粒体DNA缺陷型细胞）进行RNA提取，并在Affymetrix基因芯片上完成杂交实验。本研究检测了应激条件下癌细胞的未折叠蛋白反应（UPR）。
缩略词列表：AA：抗霉素A（antimycin A）；Bu：丁双胍（buformin）；Met：二甲双胍（metformin）；Phen：苯乙双胍（phenformin）；Rot：鱼藤酮（rotenone）；VST：维司普洛司他汀（versipelostatin）；TM：衣霉素（tunicamycin）；2DG：2-脱氧葡萄糖（2-deoxyglucose）；GS：葡萄糖饥饿（glucose starvation）。后缀_S（_S）表示包含悬浮细胞的样本上清液。