Department of Pharmacology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, United States.
Nuventra, Durham, United States.
Elife. 2020 Sep 29;9:e58108. doi: 10.7554/eLife.58108.
Cancer testis antigens (CTAs) are proteins whose expression is normally restricted to the testis but anomalously activated in human cancer. In sperm, a number of CTAs support energy generation, however, whether they contribute to tumor metabolism is not understood. We describe human COX6B2, a component of cytochrome c oxidase (complex IV). is expressed in human lung adenocarcinoma (LUAD) and expression correlates with reduced survival time. COX6B2, but not its somatic isoform COX6B1, enhances activity of complex IV, increasing oxidative phosphorylation (OXPHOS) and NAD generation. Consequently, COX6B2-expressing cancer cells display a proliferative advantage, particularly in low oxygen. Conversely, depletion of COX6B2 attenuates OXPHOS and collapses mitochondrial membrane potential leading to cell death or senescence. COX6B2 is both necessary and sufficient for growth of human tumor xenografts in mice. Our findings reveal a previously unappreciated, tumor-specific metabolic pathway hijacked from one of the most ATP-intensive processes in the animal kingdom: sperm motility.
癌症睾丸抗原（CTAs）是一类蛋白，其在正常情况下仅在睾丸中表达，但在人类癌症中异常激活。在精子中，一些 CTA 支持能量产生，然而，它们是否有助于肿瘤代谢尚不清楚。我们描述了人细胞色素 c 氧化酶（复合物 IV）的一个组成部分 COX6B2。COX6B2 在人肺腺癌（LUAD）中表达，并且表达与存活时间缩短相关。COX6B2，但不是其体细胞同工型 COX6B1，增强了复合物 IV 的活性，增加了氧化磷酸化（OXPHOS）和 NAD 的产生。因此，表达 COX6B2 的癌细胞表现出增殖优势，特别是在低氧条件下。相反，COX6B2 的耗竭会削弱 OXPHOS 并导致线粒体膜电位崩溃，导致细胞死亡或衰老。COX6B2 对于在小鼠中生长的人肿瘤异种移植物是必需的和充分的。我们的发现揭示了一种以前未被认识的、肿瘤特异性的代谢途径，该途径来自动物王国中最需要 ATP 的过程之一：精子运动。
