Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
Cancer Res. 2018 Jun 1;78(11):2799-2812. doi: 10.1158/0008-5472.CAN-17-2906. Epub 2018 Mar 29.
Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT or addition of alpha-ketoglutarate (αKG) enhanced the levels of tumor suppressors succinate dehydrogenase and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate, and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF1α, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of αKG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of αKG in TNBC cells. Together, our study has identified a novel TKT-mediated αKG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy. These findings uncover the clinical significance of TKT in breast cancer progression and metastasis and demonstrate effective therapy by inhibiting TKT or by adding αKG. .
虽然代谢重编程被认为是肿瘤发生和进展的标志，但对于调节乳腺癌转移的代谢酶和致癌代谢物知之甚少，并且很少有代谢分子被确定为潜在的治疗靶点。在这项研究中，转酮醇酶（TKT）的表达与 4T1/BALB/c 同基因模型中的肿瘤大小相关。此外，与患者的原发肿瘤或正常组织相比，TKT 表达在淋巴结转移中更高，并且高 TKT 水平与不良预后相关。TKT 的耗竭或α-酮戊二酸（αKG）的添加增强了肿瘤抑制因子琥珀酸脱氢酶和延胡索酸水合酶（FH）的水平，降低了致癌代谢物琥珀酸和延胡索酸，并进一步稳定了缺氧诱导因子脯氨酰羟化酶 2（PHD2）并降低了 HIF1α，最终抑制了乳腺癌转移。减少 TKT 或添加αKG 介导了葡萄糖代谢从糖酵解到氧化磷酸化的动态转换。TKT 抑制剂噻唑硫胺、多西他赛和阿霉素的各种组合增强了三阴性乳腺癌（TNBC）细胞的细胞死亡。此外，噻唑硫胺处理导致 TNBC 细胞中αKG 水平增加。总之，我们的研究确定了一种新的 TKT 介导的 αKG 信号通路，该通路调节乳腺癌的发生和发展，可以作为改善治疗的一种方式。这些发现揭示了 TKT 在乳腺癌进展和转移中的临床意义，并证明了通过抑制 TKT 或添加αKG 进行有效的治疗。
