Metabolic remodeling in human colorectal cancer and surrounding tissues: alterations in regulation of mitochondrial respiration and metabolic fluxes

Autor: Lyudmila Ounpuu, Aleksandr Klepinin, Kati Mado, Karoliina Heck, Tuuli Kaambre, Igor Shevchuk, Laura Truu, Vahur Valvere, Manana Kandashvili, Andrus Kaldma, Andre Koit, Anu Planken, Natalja Timohhina, Kersti Tepp, Vladimir Chekulayev
Rok vydání: 2015
Předmět:
Colorectal cancer
OXPHOS
oxidative phosphorylation
Vm
maximal respiration rate
Mitochondrion
Biochemistry
VDAC
voltage dependent anion channel
Glycolysis
Large intestine
BB-CK
– brain type creatine kinase
PCr
phosphocreatine
biology
uMtCK
ubiquitous mitochondrial creatine kinase
Respiration
VEGF
vascular endothelial growth factor
OXPHOS
Mitochondria
V0
basal respiration level
medicine.anatomical_structure
COX
cytochrome c oxidase
CRC
colorectal cancer
MI
Mitochondrial Interactosome
Human colorectal cancer
Research Article
CAT
carboxyatractyloside
ETC
electron transport chain
Biophysics
ANT
adenine nucleotide translocator
Oxidative phosphorylation
TMPD
N
N
N′
N′-tetramethyl-p-phenylenediamine
PET
positron emission tomography
Downregulation and upregulation
AP5A
diadenosine pentaphosphate
qPCR
real-time quantitative PCR
medicine
MOM
mitochondrial outer membrane
AK
adenylate kinase
Km
Michaelis–Menten constant
PEP
phosphoenolpyruvate
Energy metabolism
HK
hexokinase
medicine.disease
FDG
18-fluorodeoxyglucose
PYK
pyruvate kinase
Anaerobic glycolysis
ATP-synthasome
CIMP
CpG island methylator phenotype
Cancer research
biology.protein
Creatine kinase
BSA
bovine serum albumin
CK
creatine kinase
Zdroj: Biochemistry and Biophysics Reports
ISSN: 2405-5808
Popis: The aim of the work was to evaluate whether or not there is glycolytic reprogramming in the neighboring cells of colorectal cancer (CRC). Using postoperative material we have compared the functional capacity of oxidative phosphorylation (OXPHOS) in CRC cells, their glycolytic activity and their inclination to aerobic glycolysis, with those of the surrounding and healthy colon tissue cells. Experiments showed that human CRC cannot be considered a hypoxic tumor, since the malignancy itself and cells surrounding it exhibited even higher rates of OXPHOS than healthy large intestine. The absence of acute hypoxia in colorectal carcinomas was also confirmed by their practically equal glucose-phosphorylating capacity as compared with surrounding non-tumorous tissue and by upregulation of VEGF family and their ligands. Studies indicated that human CRC cells in vivo exert a strong distant effect on the energy metabolism of neighboring cells, so that they acquire the bioenergetic parameters specific to the tumor itself. The growth of colorectal carcinomas was associated with potent downregulation of the creatine kinase system. As compared with healthy colon tissue, the tumor surrounding cells display upregulation of OXPHOS and have high values of basal and ADP activated respiration rates. Strong differences between the normal and CRC cells in the affinity of their mitochondria for ADP were revealed; the corresponding Km values were measured as 93.6±7.7 µM for CRC cells and 84.9±9.9 µM for nearby tissue; both these apparent Km (ADP) values were considerably (by almost 3 times) lower in comparison with healthy colon tissue cells (256±34 µM).
Highlights • Human colorectal cancer is not a pure hypoxic tumor of the Warburg phenotype. • The total hexokinase activity of CRC cells is close to that in nearby tissues. • In the tumor there is overexpression of VEGFs (A, B, and C) and their receptors. • CRC has higher rates of OXPHOS as compared with healthy tissue cells. • Tumor-surrounding cells cannot fuel via a lactate shunt the growth of CRC cells.
Databáze: OpenAIRE
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