Zhang Boxi, Zheng Adi, Hydbring Per, Ambroise Gorbatchev, Ouchida Amanda Tomie, Goiny Michel, Vakifahmetoglu-Norberg Helin, Norberg Erik
Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77 Stockholm, Sweden.
Department of Oncology and Pathology, Cancercenter Karolinska Z5:0, Karolinska Institutet, 171 77 Stockholm, Sweden.
Cell Rep. 2017 Jun 13;19(11):2289-2303. doi: 10.1016/j.celrep.2017.05.067.
Molecular signatures are emerging determinants of choice of therapy for lung adenocarcinomas. An evolving therapeutic approach includes targeting metabolic dependencies in cancers. Here, using an integrative approach, we have dissected the metabolic fingerprints of lung adenocarcinomas, and we show that Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine biosynthesis, is highly expressed in a adenocarcinoma subset with poor prognosis. This subset harbors a gene signature for DNA replication and proliferation. Accordingly, models with high levels of PHGDH display rapid proliferation, migration, and selective channeling of serine-derived carbons to glutathione and pyrimidines, while depletion of PHGDH shows potent and selective toxicity to this subset. Differential PHGDH protein levels were defined by its degradation, and the deubiquitinating enzyme JOSD2 is a regulator of its protein stability. Our study provides evidence that a unique metabolic program is activated in a lung adenocarcinoma subset, described by PHGDH, which confers growth and survival and may have therapeutic implications.
分子特征正逐渐成为肺腺癌治疗方案选择的决定因素。一种不断发展的治疗方法包括针对癌症中的代谢依赖性。在此，我们采用综合方法剖析了肺腺癌的代谢指纹图谱，结果表明，丝氨酸生物合成的限速酶磷酸甘油酸脱氢酶（PHGDH）在预后较差的腺癌亚组中高度表达。该亚组具有DNA复制和增殖的基因特征。因此，高水平PHGDH的模型表现出快速增殖、迁移以及丝氨酸衍生碳向谷胱甘肽和嘧啶的选择性转运，而PHGDH的缺失对该亚组显示出强大的选择性毒性。PHGDH蛋白水平的差异由其降解决定，去泛素化酶JOSD2是其蛋白稳定性的调节因子。我们的研究提供了证据，表明在由PHGDH描述的肺腺癌亚组中激活了独特的代谢程序，该程序赋予了生长和生存能力，可能具有治疗意义
