Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA.
Biochem Biophys Res Commun. 2010 Jul 16;398(1):146-52. doi: 10.1016/j.bbrc.2010.06.057. Epub 2010 Jun 19.
Targeting specific metabolic pathways has emerged for cancer therapeutics. For melanoma, metabolic studies have solely focused on high glucose uptake. By contrast, little is known regarding addiction to glutamine. Using five melanoma lines and two normal cell types, addition of aminooxyacetate (AOA), an inhibitor of glutamate-dependent transaminase regulating glutaminolytic pathway, two lines underwent low levels of apoptosis (>30%), while the other three lines were resistant, as were normal cells to AOA. However, three resistant lines (but not normal cells), became sensitized to undergoing apoptosis when TRAIL was combined with AOA. TRAIL by itself had minimal effects on all cell lines and normal cells, and did not augment AOA-induced killing in the two sensitive melanoma lines. AOA plus TRAIL induced a caspase-dependent apoptotic response. AOA did not influence TRAIL DR4 or DR5 cell surface death receptor levels, but AOA enhanced pro-apoptotic protein levels of Noxa, while reducing pro-survival protein Mcl-1. To verify AOA was targeting glutamine pathway, depletion of glutamine produced similar results, because absence of glutamine sensitized three melanoma lines, but not fibroblasts to killing by TRAIL. Glutamine depletion also led to Noxa induction. These results indicate some lines are addicted to glutamine, and treatment with AOA or glutamine depletion sensitizes melanoma to TRAIL-mediated killing, while sparing normal cells. Future studies are indicated to translate these discoveries to metastatic melanoma as there is currently no treatment available to prolong survival.
靶向特定的代谢途径已成为癌症治疗的新策略。对于黑色素瘤，代谢研究仅集中在高葡萄糖摄取上。相比之下，对于谷氨酰胺的依赖性知之甚少。本研究使用了五种黑色素瘤细胞系和两种正常细胞类型，添加了氨基氧乙酸（AOA），一种谷氨酸依赖的转氨酶抑制剂，调节谷氨酰胺分解途径，两条细胞系经历了低水平的细胞凋亡（>30%），而其他三条细胞系以及正常细胞对 AOA 均具有抗性。然而，当 TRAIL 与 AOA 联合使用时，三种耐药细胞系（而非正常细胞）对细胞凋亡变得敏感。TRAIL 本身对所有细胞系和正常细胞的影响都很小，并且不能增强两种敏感黑色素瘤细胞系中 AOA 诱导的杀伤作用。AOA 加 TRAIL 诱导了 caspase 依赖性凋亡反应。AOA 不影响 TRAIL DR4 或 DR5 细胞表面死亡受体水平，但 AOA 增强了促凋亡蛋白 Noxa 的水平，同时降低了抗凋亡蛋白 Mcl-1 的水平。为了验证 AOA 是否靶向谷氨酰胺途径，谷氨酰胺耗竭产生了类似的结果，因为缺乏谷氨酰胺使三种黑色素瘤细胞系而非成纤维细胞对 TRAIL 诱导的杀伤作用敏感。谷氨酰胺耗竭也导致 Noxa 的诱导。这些结果表明，一些细胞系对谷氨酰胺有依赖性，用 AOA 或谷氨酰胺耗竭处理可使黑色素瘤对 TRAIL 介导的杀伤作用敏感，同时对正常细胞无害。由于目前尚无延长生存的治疗方法，未来的研究表明需要将这些发现转化为转移性黑色素瘤。
