This study aimed to characterize the ATP-synthesis by oxidative phosphorylation in colorectal cancer (CRC) and premalignant colon polyps in relation to molecular biomarkers KRAS and BRAF. This prospective study included 48 patients. Resected colorectal polyps and postoperative CRC tissue with adjacent normal tissue (control) were collected. Patients with polyps and CRC were divided into three molecular groups: KRAS mutated, BRAF mutated and KRAS/BRAF wild-type. Mitochondrial respiration in permeabilized tissue samples was observed using high resolution respirometry. ADP-activated respiration rate (Vmax) and an apparent affinity of mitochondria to ADP, which is related to mitochondrial outer membrane (MOM) permeability, were determined. Clear differences were present between molecular groups. KRAS mutated CRC group had lower Vmax values compared to wild-type; however, the Vmax value was higher than in the control group, while MOM permeability did not change. This suggests that KRAS mutation status might be involved in acquiring oxidative phenotype. KRAS mutated polyps had higher Vmax values and elevated MOM permeability as compared to the control. BRAF mutated CRC and polyps had reduced respiration and altered MOM permeability, indicating a glycolytic phenotype. To conclude, prognostic biomarkers KRAS and BRAF are likely related to the metabolic phenotype in CRC and polyps. Assessment of the tumor mitochondrial ATP synthesis could be a potential component of patient risk stratification.
Keywords: BRAF; KRAS; colorectal cancer; colorectal polyps; energy metabolism; mitochondria; oxidative phosphorylation.
Conflict of interest statement
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: primary or secondary genetic events in colorectal carcinogenesis?BMC Cancer. 2008 Sep 9;8:255. doi: 10.1186/1471-2407-8-255. BMC Cancer. 2008. PMID: 18782444 Free PMC article.
Associations of anthropometric factors with KRAS and BRAF mutation status of primary colorectal cancer in men and women: a cohort study.PLoS One. 2014 Jun 11;9(2):e98964. doi: 10.1371/journal.pone.0098964. eCollection 2014. PLoS One. 2014. PMID: 24918610 Free PMC article.
Metabolic remodeling in human colorectal cancer and surrounding tissues: alterations in regulation of mitochondrial respiration and metabolic fluxes.Biochem Biophys Rep. 2015 Aug 29;4:111-125. doi: 10.1016/j.bbrep.2015.08.020. eCollection 2015 Dec. Biochem Biophys Rep. 2015. PMID: 29124194 Free PMC article.
Are KRAS/BRAF mutations potent prognostic and/or predictive biomarkers in colorectal cancers?Anticancer Agents Med Chem. 2012 Feb;12(2):163-71. doi: 10.2174/187152012799014968. Anticancer Agents Med Chem. 2012. PMID: 22043994 Free PMC article. Review.
Immunohistochemistry with Anti-BRAF V600E (VE1) Mouse Monoclonal Antibody is a Sensitive Method for Detection of the BRAF V600E Mutation in Colon Cancer: Evaluation of 120 Cases with and without KRAS Mutation and Literature Review.Pathol Oncol Res. 2019 Jan;25(1):349-359. doi: 10.1007/s12253-017-0344-x. Epub 2017 Nov 10. Pathol Oncol Res. 2019. PMID: 29127628 Free PMC article. Review.