Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, College of Medicine, Yonsei University, Seoul, Korea.
Br J Cancer. 2021 Feb;124(3):634-644. doi: 10.1038/s41416-020-01118-7. Epub 2020 Oct 19.
Most cancer cells employ the Warburg effect to support anabolic growth and tumorigenesis. Here, we discovered a key link between Warburg effect and aberrantly activated Wnt/β-catenin signalling, especially by pathologically significant APC loss, in CRC.
Proteomic analyses were performed to evaluate the global effects of KYA1797K, Wnt/β-catenin signalling inhibitor, on cellular proteins in CRC. The effects of APC-loss or Wnt ligand on the identified enzymes, PKM2 and LDHA, as well as Warburg effects were investigated. A linkage between activation of Wnt/β-catenin signalling and cancer metabolism was analysed in tumour of Apc mice and CRC patients. The roles of PKM2 in cancer metabolism, which depends on Wnt/β-catenin signalling, were assessed in xenograft-tumours.
By proteomic analysis, PKM2 and LDHA were identified as key molecules regulated by Wnt/β-catenin signalling. APC-loss caused the increased expression of metabolic genes including PKM2 and LDHA, and increased glucose consumption and lactate secretion. Pathological significance of this linkage was indicated by increased expression of glycolytic genes with Wnt target genes in tumour of Apc mice and CRC patients. Warburg effect and growth of xenografted tumours-induced by APC-mutated-CRC cells were suppressed by PKM2-depletion.
The β-catenin-PKM2 regulatory axis induced by APC loss activates the Warburg effect in CRC.
大多数癌细胞采用瓦博格效应来支持合成代谢生长和肿瘤发生。在这里，我们发现瓦博格效应与异常激活的 Wnt/β-连环蛋白信号之间的一个关键联系，特别是通过 CRC 中病理性显著的 APC 缺失。
进行蛋白质组学分析，以评估 KYA1797K（Wnt/β-连环蛋白信号抑制剂）对 CRC 中细胞蛋白的全局影响。研究了 APC 缺失或 Wnt 配体对鉴定出的酶 PKM2 和 LDHA 以及瓦博格效应的影响。分析了 Apc 小鼠肿瘤和 CRC 患者中 Wnt/β-连环蛋白信号激活与癌症代谢之间的联系。评估了 PKM2 在依赖 Wnt/β-连环蛋白信号的癌症代谢中的作用，在异种移植肿瘤中进行了评估。
通过蛋白质组学分析，确定 PKM2 和 LDHA 是受 Wnt/β-连环蛋白信号调节的关键分子。APC 缺失导致包括 PKM2 和 LDHA 在内的代谢基因表达增加，并增加葡萄糖消耗和乳酸分泌。在 Apc 小鼠和 CRC 患者的肿瘤中，Wnt 靶基因与糖酵解基因的表达增加表明了这种联系的病理意义。通过 APC 突变型 CRC 细胞诱导的 PKM2 耗竭，抑制了瓦博格效应和异种移植肿瘤的生长。
APC 缺失诱导的 β-连环蛋白-PKM2 调节轴激活了 CRC 中的瓦博格效应。
