APCloss induces Warburg effect via increasedPKM2transcription in colorectal cancer

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/beta-catenin signalling, especially by pathologically significantAPCloss, in CRC. Methods Proteomic analyses were performed to evaluate the global effects of KYA1797K, Wnt/beta-catenin signalling inhibitor, on cellular proteins in CRC. The effects ofAPC-loss or Wnt ligand on the identified enzymes, PKM2 and LDHA, as well as Warburg effects were investigated. A linkage between activation of Wnt/beta-catenin signalling and cancer metabolism was analysed in tumour ofApc(min/+)mice and CRC patients. The roles of PKM2 in cancer metabolism, which depends on Wnt/beta-catenin signalling, were assessed in xenograft-tumours. Results By proteomic analysis, PKM2 and LDHA were identified as key molecules regulated by Wnt/beta-catenin signalling.APC-loss caused the increased expression of metabolic genes includingPKM2andLDHA, 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 ofApc(min/+)mice and CRC patients. Warburg effect and growth of xenografted tumours-induced byAPC-mutated-CRC cells were suppressed by PKM2-depletion. Conclusions The beta-catenin-PKM2 regulatory axis induced byAPCloss activates the Warburg effect in CRC.