“Warburg effect (oncology)”的意思、由来-开放百科全书

In oncology, the Warburg effect ({{IPAc-en|ˈ|v|ɑr|b|ʊər|g}}) refers to the observation that even in aerobic conditions, cancer cells tend to favor metabolism via glycolysis rather than the much more efficient oxidative phosphorylation pathway which is the preference of most other cells of the body.^[1] In tumor cells, last product of glycolysis, pyruvate, is then converted into lactate. This observation was first made by Nobel laureate Otto Heinrich Warburg^[2] who was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme".^[3]

Warburg's research

Around the 1920s, Otto Heinrich Warburg and his group concluded that deprivation of glucose and oxygen in tumor cells leads to lack of energy resulting in cell death. Biochemist Herbert Grace Crabtree further extended Warburg's research by discovering environmental or genetic influences. Crabtree observed that yeast, Saccharomyces cerevisiae, prefers glycolysis leading to ethanol production over oxidative phosphorylation in aerobic conditions and presence of high concentration of glucose - Crabtree effect. Warburg observed similar phenomenon in tumors - cancer cells tend to use glycolysis for obtaining energy even in aerobic conditions - coining a term "aerobic glycolysis". The phenomenon was later termed Warburg effect after its discoverer.^[4] Warburg also hypothesized that dysfunctional mitochondria may be the cause of higher rate of glycolysis, as well as predominant cause of cancer development.^[5]

Basis

Normal cells primarily produce energy through mitochondrial oxidative phosphorylation. However, most cancer cells predominantly produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Aerobic glycolysis is less efficient than oxidative phosphorylation in terms of adenosine triphosphate production, but leads to the increased generation of additional metabolites that may particularly benefit proliferating cells.^[4]

The Warburg effect has been much studied, but its precise nature remains unclear, which hampers the beginning of any work that would explore its therapeutic potential.^[5]

Diagnostically the Warburg effect is the basis for the PET scan in which an injected radioactive glucose analog is detected at higher concentrations in malignant cancers than in other tissues.^[6]

Otto Warburg postulated this change in metabolism is the fundamental cause of cancer,^[7] a claim now known as the Warburg hypothesis. Today, mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation, and the Warburg effect is considered to be a result of these mutations rather than a cause.^[8]^[9]

Possible explanations

The Warburg effect may simply be a consequence of damage to the mitochondria in cancer, or an adaptation to low-oxygen environments within tumors, or a result of cancer genes shutting down the mitochondria, which are involved in the cell's apoptosis program that kills cancer cells. It may also be an effect associated with cell proliferation. Since glycolysis provides most of the building blocks required for cell proliferation, cancer cells (and normal proliferating cells) have been proposed to need to activate glycolysis, despite the presence of oxygen, to proliferate.^[10]

Evidence attributes some of the high anaerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase^[11] responsible for driving the high glycolytic activity. In kidney cancer, this effect could be due to the presence of mutations in the von Hippel–Lindau tumor suppressor gene upregulating glycolytic enzymes, including the M2 splice isoform of pyruvate kinase.^[12] TP53 mutation hits energy metabolism and increases glycolysis in breast cancer.^[13]

The Warburg effect is associated with glucose uptake and utilization, as this ties into how mitochondrial activity is regulated. The concern lies less in mitochondrial damage and more in the change in activity. On the other hand, tumor cells exhibit increased rates of glycolysis which can be explained with mitochondrial damage.^[14]

In March 2008, Lewis C. Cantley and colleagues announced that the tumor M2-PK, a form of the pyruvate kinase enzyme, gives rise to the Warburg effect. Tumor M2-PK is produced in all rapidly dividing cells and is responsible for enabling cancer cells to consume glucose at an accelerated rate; on forcing the cells to switch to pyruvate kinase's alternative form by inhibiting the production of tumor M2-PK, their growth was curbed. The researchers acknowledged the fact that the exact chemistry of glucose metabolism was likely to vary across different forms of cancer; however, PKM2 was identified in all of the cancer cells they had tested. This enzyme form is not usually found in healthy tissue, though it is apparently necessary when cells need to multiply quickly, e.g., in healing wounds or hematopoiesis.^[15]^[16]

Glycolytic inhibitors

Many substances have been developed which inhibit glycolysis, and such inhibitors are currently the subject of intense research as anticancer agents,^[17] including SB-204990, 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3-BrPA, bromopyruvic acid, or bromopyruvate), 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), 5-thioglucose and dichloroacetic acid (DCA). Clinical trial for 2-DG [2008] showed slow accrual and was terminated.^[18] There is no evidence yet [2012] to support the use of DCA for cancer treatment.^[19]

Alpha-cyano-4-hydroxycinnamic acid (ACCA;CHC), a small-molecule inhibitor of monocarboxylate transporters (MCTs; which prevent lactic acid build up in tumors) has been successfully used as a metabolic target in brain tumor pre-clinical research.^[20]^[21]^[22]^[23] Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.^[24]

Dichloroacetic acid (DCA), a small-molecule inhibitor of mitochondrial pyruvate dehydrogenase kinase, "downregulates" glycolysis in vitro and in vivo. Researchers at the University of Alberta theorized in 2007 that DCA might have therapeutic benefits against many types of cancer.^[25]^[26]

Pyruvate dehydrogenase catalyses the rate-limiting step in the aerobic oxidation of glucose and pyruvate and links glycolysis to the tricarboxylic acid cycle (TCA). DCA acts a structural analog of pyruvate and activates the pyruvate dehydrogenase complex (PDC) to inhibit pyruvate dehydrogenase kinases, to keep the complex in its un-phosphorylated form. DCA reduces expression of the kinases, preventing the inactivation of the PDC, allowing the conversion of pyruvate to acetyl-CoA rather than lactate through anaerobic respiration, thereby permitting cellular respiration to continue. Through this mechanism of action, DCA works to counteract the increased production of lactate exhibited by tumor cells by enabling the TCA cycle to metabolse it by oxidative phosphorylation. ^[27] DCA has not been evaluated as a sole cancer treatment yet, as research on the clinical activity of the drug is still in progress, but it has been shown to be effective when used with other cancer treatments. The neurotoxicity and pharmacokinetics of the drug still need to be monitored but if its evaluations are satisfactory it could be very useful as it is an inexpensive small molecule. ^[28]

Blood glucose levels

High glucose levels have been shown to accelerate cancer cell proliferation in vitro, while glucose deprivation has led to apoptosis {{citation needed|date=March 2019}}. These findings have initiated further study of the effects of carbohydrate restriction on tumor growth. Clinical evidence shows that lower blood glucose levels in late-stage cancer patients have been correlated with better outcomes.^[29]

Alternative models

A model called the "reverse Warburg effect" describes cells producing energy by glycolysis, but which are not tumor cells, but stromal fibroblasts.^[30] In this scenario, the stroma become corrupted by cancer cells and turn into factories for the synthesis of energy rich nutrients. The cells then take these energy rich nutrients and use them for TCA cycle which is used for oxidative phosphorylation. This results in an energy rich environment that allows for replication of the cancer cells. This still supports Warburg's original observation that tumors show a tendency to create energy through anaerobic glycolysis. ^[31]

Cancer metabolism and epigenetics

Nutrient utilization is dramatically altered when cells receive signals to proliferate. Characteristic metabolic changes enable cells to meet the large biosynthetic demands associated with cell growth and division. Changes in rate-limiting glycolytic enzymes redirect metabolism to support growth and proliferation. Metabolic reprogramming in cancer is largely due to oncogenic activation of signal transduction pathways and transcription factors. Although less well understood, epigenetic mechanisms also contribute to the regulation of metabolic gene expression in cancer. Reciprocally, accumulating evidence suggest that metabolic alterations may affect the epigenome. Understanding the relation between metabolism and epigenetics in cancer cells may open new avenues for anti-cancer strategies.^[32]

Drug research

Warburg effect in non-cancer cells

Activated T lymphocytes have many times higher demand for energy than quiscent ones. The energy is primarily used for proliferation, diferentiation and various effector mechanisms (for example cytokine production). Therefore rapid increase in metabolism is needed during activation of T lymphocyte. Peripheral blood, habitat of activated T lymphocytes, stable concentration of glucose offers an opportutiny of switch to fast utilization of glucose, whereas key role plays coreceptor CD28.^[34] Studies reveal a parallel between insulin and CD3/CD28 signalling. Both leads to higher expression and exposition of glucose transporter 1 (Glut-1) on cell surface via activation of Akt kinase. Moreover CD28 signal transduction leads not only to higher glucose uptake but even higher rate of glycolysis. Most of glucose taken by activated T lymphocytes is metabolised to lactate and dumped out of the cells.^[35] In conclusion activated T lympocytes show higher uptake of glucose and prefer glycolysis from oxidative phosphorylation in aerobic conditions. These findings suggest that Warburg metabolism is rather physiological phenomenon than unique to cancer cells.

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