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 Apcmin/+ 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 Apcmin/+ 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.
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Ethics approval and consent to participate
All animal experiments were performed in accordance with Korean Food and Drug Administration guidelines. Protocols were reviewed and approved by the Institutional Review Board of Severance Hospital, Yonsei University College of Medicine.
Consent for publication
The datasets generated and/or analysed during the current study are available through Gene expression omnibus (GEO) or the corresponding references. Data of the microarray analysis: Gene Expression. Data of the microarray analysis on normal tissues and adenoma of small intestine tissues from WT and Apcmin/+ mice are shown in Fig. 2c and Fig. S3a: GSE422. Data of the microarray analysis on human normal colon and CRC samples are shown in Fig. S3b: GSE9348. Enrichment of glycolysis and glyconeogenesis in human tissues of normal mucosa and colorectal adenomas is shown in Fig. 2h (left panel): GSE8671. Enrichment of glycolysis and glyconeogenesis in CRC patients with and without APC mutations is shown in Fig. 2h (right panel): GSE26906. Gene expression of LDHA, AXIN2 and MYC in human CRC samples harbouring WT and MT APC in Fig. 3g: GSE63624.
The authors declare no competing interests.
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.
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Cha, PH., Hwang, JH., Kwak, DK. et al. APC loss induces Warburg effect via increased PKM2 transcription in colorectal cancer. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-01118-7