Metabolic control analysis of respiration in human cancer tissue

Tuuli Kaambre,Kersti Tepp,Rita Guzun,Natalja Timohhina,Minna Varikmaa,Vahur Valvere,Andre Koit,Valdur Saks,Igor Shevchuk,Rafaela Bagur,Aleksandr Klepinin,Vladimir Chekulayev,Tiia Anmann,Andrus Kaldma

doi:10.3389/fphys.2013.00151

Tuuli Kaambre, Kersti Tepp + Show 12 more

Open Access

https://doi.org/10.3389/fphys.2013.00151

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Abstract

Bioenergetic profiling of cancer cells is of great potential because it can bring forward new and effective therapeutic strategies along with early diagnosis. Metabolic Control Analysis (MCA) is a methodology that enables quantification of the flux control exerted by different enzymatic steps in a metabolic network thus assessing their contribution to the system‘s function. Our main goal is to demonstrate the applicability of MCA for in situ studies of energy metabolism in human breast and colorectal cancer cells as well as in normal tissues. We seek to determine the metabolic conditions leading to energy flux redirection in cancer cells. A main result obtained is that the adenine nucleotide translocator exhibits the highest control of respiration in human breast cancer thus becoming a prospective therapeutic target. Additionally, we present evidence suggesting the existence of mitochondrial respiratory supercomplexes that may represent a way by which cancer cells avoid apoptosis. The data obtained show that MCA applied in situ can be insightful in cancer cell energetic research.

Highlights

Oncologic diseases such as breast and colorectal cancers are still one of the main causes of premature death among people
Our previous studies showed that the mitochondrial-bound creatine kinase (CK) (MtCK) activity was significantly decreased in HL-1 tumor cells (Monge et al, 2009), as compared to normal parent cardiac cells where the oxidative phosphorylation (OXPHOS) is the main ATP source of and the CK system is a main energy carrier
BIOENERGETIC PROFILING OF HUMAN CANCER AND Metabolic Control Analysis (MCA) First, we evaluated the impact of Cr, ADP, mitochondrial-bound hexokinase (HK) and CK reactions on OXPHOS in permeabilized human tumor samples

Summary

Introduction

Oncologic diseases such as breast and colorectal cancers are still one of the main causes of premature death among people. Current knowledge supports the idea that human breast and colorectal cancer cells exhibit increased rates of glucose consumption displaying a Warburg phenotype, i.e., elevated glycolysis even in the presence of oxygen (Warburg and Dickens, 1930; Warburg, 1956; Izuishi et al, 2012). Notwithstanding, there are some evidences that in these malignancies mitochondrial oxidative phosphorylation (OXPHOS) is the main source of ATP rather than glycolysis. Our current knowledge about the function of CK/creatine (Cr) system in human breast and colorectal cancer is insufficient. Our previous studies showed that the mitochondrial-bound CK (MtCK) activity was significantly decreased in HL-1 tumor cells (Monge et al, 2009), as compared to normal parent cardiac cells where the OXPHOS is the main ATP source of and the CK system is a main energy carrier. We estimated the role of MtCK in maintaining energy homeostasis in human colorectal cancer cells

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