Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps.

Egle Rebane-Klemm,Tuuli Kaambre,Jelena Bogovskaja,Leenu Reinsalu,Vahur Valvere,Marju Puurand,Külliki Suurmaa,Vladimir Afanasjev,Natalja Timohhina,Vladimir Chekulayev,Kersti Tepp,Igor Shevchuk,Laura Truu

doi:10.3390/cancers12040815

Abstract

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.

Highlights

Colorectal cancer (CRC) is the leading cause of premature cancer death worldwide, prompting the urgent need to develop more effective treatment strategies
Cancer metabolism profoundly differs from normal cellular metabolism, and interrelated connections between cancer mitochondrial respiration and oncogenic driver genes like KRAS and BRAF are relatively unexplored
The KRAS mutation is an early event in colorectal cancer (CRC) and most KRAS mutations are located in codons 12 and 13

Summary

Introduction

Colorectal cancer (CRC) is the leading cause of premature cancer death worldwide, prompting the urgent need to develop more effective treatment strategies. CRC is a heterogeneous disease and presents distinct subtypes with different molecular and pathological features. The majority of sporadic CRC typically develops progressively from premalignant precursor lesions, known as polyps, to malignant tumors. Most colorectal polyps are harmless, but some can develop (by not fully understood mechanisms) into malignant invasive adenocarcinomas. CRC is triggered by various molecular events in several proto-oncogenes (such as the PIK3CA, p53, KRAS, BRAF and c-MYC genes) and tumor suppressor genes (such as the APC, PTEN, SMAD4 genes) [1,2,3]. A better understanding of the pathogenesis of CRC, the metabolic heterogeneity of emerging polyps and potential drivers is very important to develop new prognostic markers and successful agents for the prevention and treatment of this disease

Objectives

Methods

Results

Conclusion