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

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Authors: Pu-Hyeon Cha ; Jeong-Ha Hwang ; Dong-Kyu Kwak ; Eunjin Koh ; Kyung-Sup Kim ; Kang-Yell Choi

MeSH: Animals ; Carrier Proteins / genetics ; Carrier Proteins / metabolism* ; Colorectal Neoplasms / genetics ; Colorectal Neoplasms / metabolism* ; Genes, APC* ; Heterografts ; Humans ; L-Lactate Dehydrogenase / genetics ; L-Lactate Dehydrogenase / metabolism* ; Male ; Membrane Proteins / genetics ; Membrane Proteins / metabolism* ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondrial Proton-Translocating ATPases / metabolism ; Neoplasm Proteins / genetics ; Neoplasm Proteins / metabolism* ; Proteomics ; Thiazolidines / pharmacology ; Thyroid Hormones / genetics ; Thyroid Hormones / metabolism* ; Tissue Array Analysis ; Warburg Effect, Oncologic* ; Wnt Signaling Pathway* / drug effects ; Wnt Signaling Pathway* / genetics ; beta Catenin / metabolism

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 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.