Warburg effect

The phrase "Warburg effect" (/ˈvɑːrbʊərɡ/) is used for two unrelated observations in biochemistry, one in plant physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.

Plant physiology

In plant physiology, the Warburg's effect is the decrease in the rate of photosynthesis by high oxygen concentrations.^[1][2] Oxygen is a competitive inhibitor of the carbon dioxide fixation by RuBisCO which initiates photosynthesis. Furthermore, oxygen stimulates photorespiration which reduces photosynthetic output. These two mechanisms working together are responsible for the Warburg effect.^[3]

Oncology

Basis

In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol,^[4] rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.^[5][6][7] The latter process is aerobic (uses oxygen). Malignant, rapidly growing tumor cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful.

Otto Warburg postulated this change in metabolism is the fundamental cause of cancer,^[8] 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.^[9][10]

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 because they are involved in the cell's apoptosis program which would otherwise kill cancerous 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.^[11] Evidence attributes some of the high aerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase^[12] 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.^[13]

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; but 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.^[14][15]

Glycolytic inhibitors

Many substances have been developed which inhibit glycolysis, and such inhibitors are currently the subject of intense research as anticancer agents,^[16] including SB-204990, 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3-BrPA, bromopyruvic acid, or bromopyruvate), 3-BrOP, 5-thioglucose and dichloroacetic acid (DCA). Clinical trials are ongoing for 2-DG and DCA.^[17]

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.^{[18][19][20][21]} Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.^[22]

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 cancers.^[23][24]

Blood glucose levels

High glucose levels have been shown to accelerate cancer cell proliferation in vitro, while glucose deprivation has led to apoptosis. 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.^[25]

Alternative models

A model called the reverse Warburg effect describes cells producing energy by glycolysis, but were not tumor cells, but stromal fibroblasts. Although the Warburg effect would exist in certain cancer types potentially, it highlighted the need for a closer look at tumor metabolism.^[26][27]

Metabolic reprogramming is also observed in neurodegenerative diseases, Alzheimer's and Parkinson's. This metabolic alteration is described by the up-regulation of oxidative phosphorylation - called the inverse Warburg Effect.

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.^[28]

References