APC loss induces Warburg effect via increased PKM2 transcription in colorectal cancer

Abstract 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 Apc min/+ 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 Apc min/+ 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.