Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
Nat Commun. 2024 Aug 28;15(1):7455. doi: 10.1038/s41467-024-51444-0.
Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.
脂肪酸合成增加有利于神经胶质瘤的恶性程度。然而，细胞溶质乙酰辅酶 A 产生的协调调节，脂肪酸合成的唯一底物，仍然不清楚。在这里，我们表明原癌基因酪氨酸激酶 c-SRC 在神经胶质瘤中被激活，并重塑细胞溶质乙酰辅酶 A 产生以用于脂肪酸合成。首先，醋酸盐是神经胶质瘤中脂肪酸合成的重要底物。c-SRC 通过磷酸化乙酰辅酶 A 合成酶 ACSS2 上的 Tyr530 和 Tyr562 来刺激醋酸盐向细胞质中乙酰辅酶 A 的转化。其次，c-SRC 通过磷酸化三羧酸循环酶柠檬酸裂解酶 ACLY 上的 Tyr682 来抑制柠檬酸衍生的乙酰辅酶 A 合成。ACLY 磷酸化将柠檬酸转移到 IDH1 催化的 NADPH 产生，为脂肪酸合成提供还原当量。ACSS2 和 ACLY 的 c-SRC 无反应性双突变显著减少脂肪酸合成，并阻碍神经胶质瘤的进展。总之，这种重塑满足了神经胶质瘤细胞在脂肪酸合成中对乙酰辅酶 A 和 NADPH 的双重需求，并为通过抑制 c-SRC 治疗神经胶质瘤提供了证据。
