Dynamic bioenergetic alterations in colorectal adenomatous polyps and adenocarcinomas

Wey Ran Lin*, Jy Ming Chiang, Siew Na Lim, Ming Yao Su, Tsung Hsing Chen, Shu Wei Huang, Chun Wei Chen, Ren Chin Wu, Chia Lung Tsai, Yang Hsiang Lin, Malcolm R. Alison, Sen Yung Hsieh, Jau Song Yu, Cheng Tang Chiu, Chau Ting Yeh

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

19 Scopus citations

Abstract

Background: Energy metabolism in carcinogenesis is poorly understood. It is widely accepted the majority of colorectal cancers (CRCs) arise from adenomatous polyps (APs). We aimed to characterize the bioenergetic alterations in APs and CRCs. Methods: Fifty-six APs, 93 CRCs and adjacent normal mucosae were tested. Oxygen consumption rate (OCR) was measured representing mitochondrial oxidative phosphorylation (OxPhos), and extracellular acidification rate (ECAR)was measured representing glycolysis. Mitochondrial DNA (mtDNA) variants and mutations were studied. Over-expressed metabolic genes in APs were identified by microarray and validated by qRT-PCR, Western blots and immunohistochemistry. Identified genes were knocked down in WiDr and colo205 CRC cell lines, and their expression was analyzed in APs/CRCs with enhanced glycolysis. Findings: ECAR, not OCR, was significantly increased in APs. While no difference of ECAR was found between CRCs and normal mucosae, OCR was significantly reduced in CRCs. OCR/ECAR ratio was decreased in APs over 1 cm, APs with a villous component and CRCs, indicating their glycolytic tendencies. The number of mtDNA mutations was increased in APs and CRCs, but not correlated with metabolic profiles. Two metabolic genes ALDOB and SLC16A4 were up-regulated in APs. Both ALDOB-knockdown and SLC16A4-knockdown CRC cell lines showed increased basal motichondrial OxPhos and decreased basal glycolysis. Moreover, the increase of mitochondrial ATP-linked respiration and the decrease of glycolytic capacity were showed in SLC16A4-knockdown cells. Finally, APs/CRCs with enhanced glycolysis had increased SLC16A4 expression. Interpretation: ATP production shifts from OxPhos to glycolysis in the process of AP enlargement and villous transformation. OxPhos defects are present in CRCs but not in APs. APs and CRCs tend to accumulate mtDNA mutations, but these are not correlated with bioenergetic profiles. Finally, the ALDOB and SLC16A4 may contribute to the glycolytic shift in APs/CRCs.

Original languageEnglish
Pages (from-to)334-345
Number of pages12
JournalEBioMedicine
Volume44
DOIs
StatePublished - 06 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Keywords

  • Bioenergetics
  • Colorectal adenomatous polyp
  • Colorectal cancer
  • Glycolysis
  • Mitochondrial oxidative phosphorylation

Fingerprint

Dive into the research topics of 'Dynamic bioenergetic alterations in colorectal adenomatous polyps and adenocarcinomas'. Together they form a unique fingerprint.

Cite this