Mashimo Tomoyuki, Pichumani Kumar, Vemireddy Vamsidhara, Hatanpaa Kimmo J, Singh Dinesh Kumar, Sirasanagandla Shyam, Nannepaga Suraj, Piccirillo Sara G, Kovacs Zoltan, Foong Chan, Huang Zhiguang, Barnett Samuel, Mickey Bruce E, DeBerardinis Ralph J, Tu Benjamin P, Maher Elizabeth A, Bachoo Robert M
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cell. 2014 Dec 18;159(7):1603-14. doi: 10.1016/j.cell.2014.11.025.
Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using (13)C-NMR analysis of brain tumors resected from patients during infusion of (13)C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-(13)C]acetate and can do so while simultaneously oxidizing [1,6-(13)C]glucose. The tumors do not oxidize [U-(13)C]glutamine. In vivo oxidation of [1,2-(13)C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth.
胶质母细胞瘤和脑转移瘤是增殖性很强的脑肿瘤，患者存活时间短。此前，我们在输注¹³C-葡萄糖期间，对从患者身上切除的脑肿瘤进行¹³C-NMR分析，结果表明，柠檬酸循环中葡萄糖有活跃的氧化过程，但葡萄糖对乙酰辅酶A池的碳贡献不到50%。在此，我们发现原发性和转移性小鼠原位脑肿瘤有能力氧化[1,2-(¹³C)]乙酸盐，并且在同时氧化[1,6-(¹³C)]葡萄糖时也能做到这一点。肿瘤不会氧化[U-(¹³C)]谷氨酰胺。在脑肿瘤患者体内验证了[1,2-(¹³C)]乙酸盐的氧化，并与乙酰辅酶A合成酶2（ACSS2）的表达相关。这些数据共同表明，不同脑肿瘤中存在一种显著常见的代谢表型，包括在柠檬酸循环中氧化乙酸盐的能力。这种适应性对于满足恶性生长对生物合成和生物能量的高需求可能很重要。
