Gdynia Georg, Sauer Sven W, Kopitz Jürgen, Fuchs Dominik, Duglova Katarina, Ruppert Thorsten, Miller Matthias, Pahl Jens, Cerwenka Adelheid, Enders Markus, Mairbäurl Heimo, Kamiński Marcin M, Penzel Roland, Zhang Christine, Fuller Jonathan C, Wade Rebecca C, Benner Axel, Chang-Claude Jenny, Brenner Hermann, Hoffmeister Michael, Zentgraf Hanswalter, Schirmacher Peter, Roth Wilfried
Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.
German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology, 69120 Heidelberg, Germany.
Nat Commun. 2016 Mar 7;7:10764. doi: 10.1038/ncomms10764.
The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense. Here we show that natural killer cell-derived HMGB1 directly eliminates cancer cells by triggering metabolic cell death. HMGB1 allosterically inhibits the tetrameric pyruvate kinase isoform M2, thus blocking glucose-driven aerobic respiration. This results in a rapid metabolic shift forcing cells to rely solely on glycolysis for the maintenance of energy production. Cancer cells can acquire resistance to HMGB1 by increasing glycolysis using the dimeric form of PKM2, and employing glutaminolysis. Consistently, we observe an increase in the expression of a key enzyme of glutaminolysis, malic enzyme 1, in advanced colon cancer. Moreover, pharmaceutical inhibition of glutaminolysis sensitizes tumour cells to HMGB1 providing a basis for a therapeutic strategy for treating cancer.
高迁移率族蛋白B1（HMGB1）在免疫抗肿瘤防御中起核心作用。我们在此表明，自然杀伤细胞衍生的HMGB1通过触发代谢性细胞死亡直接消除癌细胞。HMGB1变构抑制四聚体丙酮酸激酶同工型M2，从而阻断葡萄糖驱动的有氧呼吸。这导致快速的代谢转变，迫使细胞仅依靠糖酵解来维持能量产生。癌细胞可以通过使用二聚体形式的PKM2增加糖酵解并采用谷氨酰胺分解来获得对HMGB1的抗性。一致地，我们观察到晚期结肠癌中谷氨酰胺分解关键酶苹果酸酶1的表达增加。此外，谷氨酰胺分解的药物抑制使肿瘤细胞对HMGB1敏感，为癌症治疗策略提供了基础。
