Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

Cancers

Jelena Bogovskaja¹  Vladimir Afanasjev²  Külliki Suurmaa³  Kersti Tepp⁴  Egle Rebane-Klemm⁴  Tuuli Kaambre⁴  Igor Shevchuk⁴  Laura Truu⁴  Leenu Reinsalu⁴  Natalja Timohhina⁴  Marju Puurand⁴  Vladimir Chekulayev⁴  Vahur Valvere⁵ 

[1] Clinic of Diagnostics at the North Estonia Medical Centre, J. Sütiste tee 19, 13419 Tallinn, Estonia;Clinic of Surgery at the North Estonia Medical Centre, J. Sütiste tee 19, 13419 Tallinn, Estonia;Department of Gastroenterology, the West Tallinn Central Hospital, Paldiski mnt 68, 10617 Tallinn, Estonia;Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia;Oncology and Haematology Clinic at the North Estonia Medical Centre, J. Sütiste tee 19, 13419 Tallinn, Estonia;

关键词: energy metabolism;    colorectal cancer;    colorectal polyps;    mitochondria;    oxidative phosphorylation;    KRAS;   

DOI  :  10.3390/cancers12040815

来源: DOAJ

【 摘 要 】

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 (V_max) 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 V_max values compared to wild-type; however, the V_max 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 V_max 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.

【 授权许可】

Unknown