厌氧糖酵解
焦点粘着
结缔组织增生
糖酵解
缺氧(环境)
生物
细胞生物学
葡萄糖摄取
肿瘤微环境
氧化磷酸化
化学
癌症研究
内分泌学
生物化学
基质
新陈代谢
信号转导
免疫学
胰岛素
有机化学
免疫组织化学
氧气
肿瘤细胞
作者
Hou-Chun Huang,Wey‐Ran Lin,Siew‐Na Lim,Chau‐Ting Yeh,Tzung‐Hai Yen,Malcolm R. Alison,Chi-Shuo Chen
标识
DOI:10.1016/j.colsurfb.2020.110969
摘要
Colorectal cancer (CRC) progression is highly associated with desmoplasia. Aerobic glycolysis is another distinct feature that appears during the CRC phase of the adenoma-carcinoma sequence. However, the interconnections between the desmoplastic microenvironment and metabolic reprogramming remain largely unexplored. In our in vitro model, we investigated the compounding influences of hypoxia and substrate stiffness, two critical physical features of desmoplasia, on the CRC metabolic shift by using engineered polyacrylamide gels. Unexpectedly, we found that compared to cells on a soft gel (approximately 1.5 kPa, normal tissue), cells on a stiff gel (approximately 8.7 kPa, desmoplastic tissue) exhibited reduced glucose uptake and glycolysis under both normoxia and hypoxia. In addition, the increasing substrate stiffness activated focal adhesion kinase (FAK)/phosphoinositide 3-kinase signaling, but not the mitochondrial respiratory inhibitor HIF-1α. However, the presence of aldolase B (ALDOB) reversed the CRC metabolic response to mechanosignaling; enhanced glucose uptake (approximately 1.5-fold) and aerobic glycolysis (approximately 2- to 3--fold) with significantly decreased mitochondrial oxidative phosphorylation. ALDOB also changed the response of CRC traction force, which is related to tumor metastasis, under hypoxia/normoxia. In summary, our data suggest a counter influence of hypoxia and substrate stiffness on glucose uptake, and ALDOB upregulation can reverse this, which drives hypoxia and stiff substrate to enhance the CRC aerobic glycolysis synergistically. The results not only highlight the potential impacts on metabolic reprogramming led by physical alterations in the microenvironment, but also extend our understanding of the essential role of ALDOB in CRC progression from a biophysical perspective.
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