Molecular Pathways: Targeting Cellular Energy Metabolism in Cancer via Inhibition of SLC2A1 and LDHA.
Molecular Pathways: Targeting Cellular Energy Metabolism in Cancer via Inhibition of SLC2A1 and LDHA.
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DOI：
10.1158/1078-0432.ccr-14-1209
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发表时间：
2015-06-01
期刊：
影响因子：
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通讯作者：
Gomperts BN
中科院分区：
文献类型：
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作者：
Ooi AT;Gomperts BN
细胞能量代谢的重新编程被广泛认为是癌症的主要标志之一。癌细胞中糖酵解途径关键调节因子的异常表达模式证实了这样的假设：大多数癌细胞利用有氧糖酵解作为其主要 ATP 生产方法，而不是线粒体氧化磷酸化。在肺癌患者的癌前病变和肿瘤中检测到SLC2A1和LDHA这两种糖酵解途径的重要调节因子的过度表达，表明这些蛋白参与癌症的早期癌变和肿瘤进展。临床前研究表明，抑制 SLC2A1 或 LDHA 会导致体外和体内肿瘤生长减少。 SLC2A1 和 LDHA 抑制剂与其他化疗药物联合使用时，可通过使化疗耐药的癌细胞对化疗重新敏感而显示出协同抗肿瘤作用。这些结果表明，破坏癌细胞能量学中的 SLC2A1、LDHA 或其他调节因子是一种非常有前途的新靶向治疗方法。
Reprogramming of cellular energy metabolism is widely accepted to be one of the main hallmarks of cancer. Aberrant expression pattern of key regulators in the glycolysis pathway in cancer cells corroborates with the hypothesis that most cancer cells utilize aerobic glycolysis as their main ATP production method instead of mitochondrial oxidative phosphorylation. Overexpression of SLC2A1 and LDHA, both important regulators of the glycolysis pathway, was detected in the premalignant lesions and tumors of lung cancer patients, suggesting the involvements of these proteins in early carcinogenesis and tumor progression in cancer. Preclinical studies demonstrated that inhibiting SLC2A1 or LDHA led to diminished tumor growth in vitro and in vivo. SLC2A1 and LDHA inhibitors, when administered in combination with other chemotherapeutic agents, showed synergistic antitumor effects by re-sensitizing chemo-resistant cancer cells to the chemotherapies. These results indicate that disrupting SLC2A1, LDHA, or other regulators in cancer cell energetics is a very promising approach for new targeted therapies.