Aglycemic growth enhances carbohydrate metabolism and induces sensitivity to menadione in cultured tumor-derived cells.
Aglycemic growth enhances carbohydrate metabolism and induces sensitivity to menadione in cultured tumor-derived cells.
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DOI：
10.1186/s40170-021-00241-0
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发表时间：
2021-01-19
影响因子：
5.9
通讯作者：
Neufer PD
中科院分区：
文献类型：
--
作者：
Schmidt CA;McLaughlin KL;Boykov IN;Mojalagbe R;Ranganathan A;Buddo KA;Lin CT;Fisher-Wellman KH;Neufer PD
肝细胞癌（HCC）是最常见的肝脏恶性肿瘤，由于症状出现较晚，预后较差。晚期HCC的治疗在很大程度上依赖于化疗药物，其中许多靶向细胞能量代谢。用于测试候选化疗化合物的关键平台是啮齿动物中的肝内原位异种移植物（IOX）模型。从IOX模型到临床使用的转化功效（部分）受限于肿瘤衍生细胞的代谢表型的变化，所述肿瘤衍生细胞的代谢表型的变化可通过选择性适应传代培养条件而诱导。在这项研究中，利用结合显微镜、呼吸测量、电位测定和细胞外通量分析（EFA）的详细多层次系统方法来检查肝癌衍生（HEPG 2）细胞在无血糖生长培养基条件下发生的代谢适应。我们假设，无糖酵解的增长将导致适应性的“有氧平衡”，其特征是在一系列生理能量需求状态下增强氧化磷酸化能力。无糖生长并没有引起线粒体含量、网络复杂性或内在功能能力/效率的适应性变化。在完整的细胞中，无糖酵解生长显着增强发酵糖酵解底物水平磷酸化葡萄糖再喂养过程中，并提高了反应的发酵和氧化磷酸化刺激的能量需求。此外，与对照细胞相比，无糖生长诱导HEPG 2细胞对维生素原甲萘醌的敏感性降低了25倍。这些发现表明，生长培养基条件对传代培养的肿瘤衍生细胞的能量代谢具有实质性影响，这可能对IOX测试板中掺入期间的化疗敏感性具有显著影响。此外，本研究中使用的代谢表型分析方法提供了一个实用的工作流程，可以与IOX筛查实践相结合，以帮助破译化疗药物敏感性的代谢基础。在线版本包含补充材料，可通过10.1186/s40170-021-00241-0获得。
Hepatocellular carcinoma (HCC) is the most prevalent form of liver malignancy and carries poor prognoses due to late presentation of symptoms. Treatment of late-stage HCC relies heavily on chemotherapeutics, many of which target cellular energy metabolism. A key platform for testing candidate chemotherapeutic compounds is the intrahepatic orthotopic xenograft (IOX) model in rodents. Translational efficacy from the IOX model to clinical use is limited (in part) by variation in the metabolic phenotypes of the tumor-derived cells that can be induced by selective adaptation to subculture conditions. In this study, a detailed multilevel systems approach combining microscopy, respirometry, potentiometry, and extracellular flux analysis (EFA) was utilized to examine metabolic adaptations that occur under aglycemic growth media conditions in HCC-derived (HEPG2) cells. We hypothesized that aglycemic growth would result in adaptive “aerobic poise” characterized by enhanced capacity for oxidative phosphorylation over a range of physiological energetic demand states. Aglycemic growth did not invoke adaptive changes in mitochondrial content, network complexity, or intrinsic functional capacity/efficiency. In intact cells, aglycemic growth markedly enhanced fermentative glycolytic substrate-level phosphorylation during glucose refeeding and enhanced responsiveness of both fermentation and oxidative phosphorylation to stimulated energy demand. Additionally, aglycemic growth induced sensitivity of HEPG2 cells to the provitamin menadione at a 25-fold lower dose compared to control cells. These findings indicate that growth media conditions have substantial effects on the energy metabolism of subcultured tumor-derived cells, which may have significant implications for chemotherapeutic sensitivity during incorporation in IOX testing panels. Additionally, the metabolic phenotyping approach used in this study provides a practical workflow that can be incorporated with IOX screening practices to aid in deciphering the metabolic underpinnings of chemotherapeutic drug sensitivity. The online version contains supplementary material available at 10.1186/s40170-021-00241-0.
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影响因子：
5.6
作者：
Domenis R;Bisetto E;Rossi D;Comelli M;Mavelli I
通讯作者：
Mavelli I
影响因子：
2.9
作者：
FREI, B;WINTERHALTER, KH;RICHTER, C
通讯作者：
RICHTER, C
影响因子：
2.9
作者：
Glancy, Brian;Willis, Wayne T.;Balaban, Robert S.
通讯作者：
Balaban, Robert S.
影响因子：
5.9
作者：
Epstein T;Xu L;Gillies RJ;Gatenby RA
通讯作者：
Gatenby RA
影响因子：
8.8
作者：
Fisher-Wellman KH;Davidson MT;Narowski TM;Lin CT;Koves TR;Muoio DM
通讯作者：
Muoio DM