Expression of transketolase‐like 1 (TKTL1) and p‐Akt correlates with the progression of cervical neoplasia
N KohrenhagenHans-Ullrich VoelkerMelanie SchmidtMichaela KappMatthias KrockenbergerTorsten FrambachJohanees DietlUlrike Kämmerer
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It is supposed that increased glycolysis is crucial for the energy supply during tumor progression. Unfortunately, the relevance of glycolysis in cervical neoplasia is unknown, but what is certain is the fact that cervical cancer shows a high expression of glucose membrane transporters, which are necessary for glucose uptake as an energy source. Transketolase-like enzyme 1 (TKTL1) and the oncogene p-Akt have been described to play an important role in glycolysis during tumorigenesis. Thus, we were interested in their expression in cervical tissue.We examined the expression of TKTL1 and p-Akt in 80 formalin-fixed, paraffin-embedded cervical specimens: 20 benign cervical tissues, 20 low-grade squamous intraepithelial lesions, 20 high-grade intraepithelial lesions, and 20 invasive squamous cell carcinomas (ISCC).Immunhistochemical analyses revealed that the intensity of the expression of TKTL1 and p-Akt increases significantly with an increase in the histopathological grade of cervical tissues.The results suggest that both TKTL1 and p-Akt play an important role in the progression of cervical neoplasia, which may be due to their impact on glycolysis.Keywords:
Tumor progression
Warburg Effect
Transketolase
Anaerobic glycolysis
Warburg Effect
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Bioenergetics
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Warburg Effect
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Abstract Mammalian cells produce energy by oxidative phosphorylation under aerobic conditions. However, in the 1920s, Otto Warburg reported the so‐called “Warburg effect” in which cancer cells produce ATP that is biased toward glycolysis rather than mitochondrial oxidative phosphorylation not only in anaerobic environment but also in aerobic environment. Glucose is converted into lactate without going into mitochondria after being metabolized in glycolysis. Compared with oxidative phosphorylation, the glycolysis has a faster ATP production rate but it is very inefficient, resulting in cancer cells consuming a large amount of glucose. Increased glucose metabolism has become a biomarker for cancer cells and has led to the development of positron emission tomography with fluorodeoxyglucose. Till date, the Warburg effect has been an inefficient system for cancer cells with regard to efficient energy production, but since the consumption of oxygen can be suppressed as the tumor grows in mass, it is thought that the Warburg effect is advantageous in this situation wherein the tumor can increase despite the lack of vessels. In addition, an increased lactate by the glycolysis causes acidosis in the microenvironment of tissues, which is thought to damage the surrounding normal tissues and favor the invasion and metastasis of cancer. Thus, Warburg effect is one of the key mechanisms for cancer development and will be the next promising target. In this review, we introduce key players that can be targeted in the Warburg effect and outline the prospects of treatment, targeting the Warburg effect in gynecological cancer.
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A cell living in an oxygen lacking environment is able to self tune its metabolic processes to survive in those hostile conditions using glucose more than oxygen for the production of the energy they need. This phenomenon discovered by Pasteur in 1860 is called anaerobic glycolysis. In 1930, Warburg discovered that once the optimal conditions were restored, healthy cells produce ATP again through cell respiration, while carcinogenic cells had definitively changed their metabolism, using glucose as main energy source. This phenomena is called Warburg effect or aerobic glycolysis. Mutation in the metabolism leads cancer cells not only to accelerate their cell cycle and therefore to increase proliferation rate, but those cells also create an acidic environment for healthy cells, thanks to the glycolysis by-product: lactic acid. The high level of lactic acid in the extracellular environment induces necrosis of healthy cells thus amplifying cancer cells invasion capacity. The aim of our work is to study how this evolutionary advantage of aerobic glycolytic tumour cells with respect to healthy cells affects tumour heterogeneity and vasculature system formation of a tumour spheroid.
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The Warburg effect is one of the hallmarks of cancer cells, characterized by enhanced aerobic glycolysis. Despite intense research efforts, its functional relevance or biological significance to facilitate tumor progression is still debatable. Hence the question persists when and how the Warburg effect contributes to carcinogenesis. Especially, the role of metabolic changes at a very early stage of tumorigenesis has received relatively little attention, and how aerobic glycolysis impacts tumor incidence remains largely unknown. Here we discuss a novel paradigm for the effect of the Warburg effect that provides a suppressive role in oncogenesis.
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Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “the Warburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H+), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO2 led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate…”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new “pH-related paradigm of cancer”, while at the same time addressing the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications.
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Aerobic glycolysis, i.e. , the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma.However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells.To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e. , the "reverse Warburg effect".Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment.This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent.Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.
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