Background: 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. Methods: 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 Apcmin/+ mice and CRC patients. The roles of PKM2 in cancer metabolism, which depends on Wnt/β-catenin signalling, were assessed in xenograft-tumours. Results: 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 Apcmin/+ mice and CRC patients. Warburg effect and growth of xenografted tumours-induced by APC-mutated-CRC cells were suppressed by PKM2-depletion. Conclusions: The β-catenin-PKM2 regulatory axis induced by APC loss activates the Warburg effect in CRC.
Bibliographical noteFunding Information:
Funding information This work was supported by the National Research Foundation (NRF) of Korea grant funded by the Korean Government (MSIP) (grant 2019R1A2C3002751 and 2016R1A5A1004694; to K-Y.C.). P-H.C., J-H.H. and D-K.K. were supported by a BK21 PLUS program.
© 2020, The Author(s), under exclusive licence to Cancer Research UK.
All Science Journal Classification (ASJC) codes
- Cancer Research