Namikawa-Kanai Haruka, Miyazaki Teruo, Matsubara Taisuke, Shigefuku Shunsuke, Ono Shotaro, Nakajima Eiji, Morishita Yukio, Honda Akira, Furukawa Kinya, Ikeda Norihiko
Department of Surgery, Tokyo Medical University Tokyo, Japan.
Department of Thoracic Surgery, Tokyo Medical University Ibaraki Medical Center Ibaraki, Japan.
Am J Cancer Res. 2020 Jul 1;10(7):2145-2159. eCollection 2020.
Energy metabolism in cancer cells is reprogrammed to meet the energy demands for cell proliferation under strict environments. In addition to the specifically activated metabolism of cancer, including the Warburg effect and glutaminolysis, most amino acids (AAs) are utilized for gluconeogenesis. Significant increases in AAs and energy metabolites in the tumor region occur in gastric and colon cancers. However, a different AA-related energy metabolism may exist in lung cancer because of the abundant blood supply to lung tissue. This study compared the profiles of AAs and their related metabolites in energy metabolism, analyzed by an HPLC-MS/MS system, between tissues from nontumor and tumor regions collected from 14 patients with non-small cell lung cancer (NSCLC). In the energic metabolism precursor categories, the glucogenic AAs, which included the pyruvate precursors (Ser, Gly, Thr, Ala, and Trp), the α-ketoglutarate precursors (Glu, Gln, and Pro) and the succinyl-CoA precursors (Val, Ile, and Met) were significantly increased in the tumor region compared to in the nontumor region. However, no significant differences existed between the two regions in the ketogenic AAs (Leu, Lys, and Tyr). These differences were not observed between the subgroups with and without diabetes mellitus in the two regions. The metabolites on the left-hand side of the TCA cycle were significantly higher in the tumor region, but no differences in metabolites in the right-hand side. The mRNA expressions of major AA transporters and cancer proliferation factors were also significantly increased in the tumor region, compared to these in their counterparts. In lung cancer, glucogenic AAs that are actively transported from circulating fluids would be predominantly utilized for gluconeogenesis, with and without diabetes mellitus. The characteristics of the AA-related metabolism would be associated with tissue-specific cell proliferation in patients with NSCLC.
癌细胞的能量代谢会被重新编程，以满足在严格环境下细胞增殖的能量需求。除了癌症中特异性激活的代谢，包括瓦伯格效应和谷氨酰胺分解代谢外，大多数氨基酸（AAs）还用于糖异生。胃癌和结肠癌的肿瘤区域中氨基酸和能量代谢物显著增加。然而，由于肺组织丰富的血液供应，肺癌中可能存在不同的与氨基酸相关的能量代谢。本研究比较了14例非小细胞肺癌（NSCLC）患者非肿瘤和肿瘤区域组织中，通过高效液相色谱-串联质谱系统分析的氨基酸及其相关代谢物在能量代谢中的谱图。在能量代谢前体类别中，与非肿瘤区域相比，肿瘤区域中糖异生氨基酸显著增加，其中包括丙酮酸前体（丝氨酸、甘氨酸、苏氨酸、丙氨酸和色氨酸）、α-酮戊二酸前体（谷氨酸、谷氨酰胺和脯氨酸）以及琥珀酰辅酶A前体（缬氨酸、异亮氨酸和蛋氨酸）。然而，生酮氨基酸（亮氨酸、赖氨酸和酪氨酸）在两个区域之间没有显著差异。在两个区域中，有和没有糖尿病的亚组之间未观察到这些差异。三羧酸循环左侧的代谢物在肿瘤区域显著更高，但右侧代谢物没有差异。与相应区域相比，肿瘤区域中主要氨基酸转运体和癌症增殖因子的mRNA表达也显著增加。在肺癌中，无论有无糖尿病，从循环液中主动转运的糖异生氨基酸将主要用于糖异生。与氨基酸相关的代谢特征将与NSCLC患者的组织特异性细胞增殖相关。
