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ldh_activity-_normal_vs_canceous_cells

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.

The metabolism of glucose, the central macronutrient, allows for energy to be harnessed in the form of ATP through the oxidation of its carbon bonds. This process is essential for sustaining all mammalian life. In mammals, the end product can be lactate or, upon full oxidation of glucose via respiration in the mitochondria, CO2. In tumors and other proliferating or developing cells, the rate of glucose uptake dramatically increases and lactate is produced, even in the presence of oxygen and fully functioning mitochondria. This process, known as the Warburg Effect  (Jasson W. Locasale).

The Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentacion in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells. 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 changed in metabolism is the fundamental cause of cancer, Today:Mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation.

The Warburg effect may simply be a consequence of:

  1. Damage to the mitochondria in cancer
  2. An adaptation to low-oxygen environments within tumors
  3. Result of cancer genes shutting down the mitochondria

Because are involved in the cell´s apoptosis program which would otherwise kill cancerous cells.

 

Instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. Cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of carcinogenesis, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen.

 

Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. (Lewis C. Cantley).

 

In multicellular organisms, most cells are exposed to a constant supply of nutrients. Survival of the organism requires control systems that prevent aberrant individuall cell proliferation when nutrient availability exceeds the levels needed to support cell division.

The Warburg Effect may present an advantage for cell growth in a multicellular environment. Acidification of the microenvironment and other metabolic crosstalk are intrigruing possibilities. Elevated glucose metabolism decreases the pH in the microenvironment drives local invasion (Estrella, V et al, Cancer Res.) An acid-mediated invasion hypothesis suggests that H+ ions secreted from cancer cells diffuse into the surrounding environment and alter the tumor-stroma interface, allowing for enhanced invasiveness .

 

Warburg´s  hypothesis was postulated by the Nobel laureate Otto Heinrich Warburg in 1924.Warburg reported a fundamental difference between normal and cancerous cells to be the ratio of glycolysis to respiration; this observation is also known as the Warburg effect.

Warburg articulated his hypothesis in a paper entitled “The Prime Cause and Prevention of Cancer”, which he presented in lecture at the meeting of the Nobel-Laureates on June 30, 1966 (Lake Constance).

Was a German physiologist, medical doctor. He served as an officer in the elite Uhlan during the First World War, and was awarded the Iron Cross for bravery. Earned his Doctor of Chemistry in Berlin in 1906.

Studies published since 2005 have shown that the Warburg effect, indeed, might lead to a promising approach in the treatment of solid tumors.

 

Besides promising human research at :

  • the Deparment of Medicine, University of Alberta led by Dr. Evangelos Michelakis other glycotic inhibitors besides DCA that hold promise include Bromopyruvic being researched
  • University of Texas, M.D. Anderson Cancer Center, 2-deoxyglucose (2-DG)
  • Emory University School of Medicine, and lactate dehydrogensase A
  • Johns Hopkins University School of Medicine

 

Links:

  • Otto Warburg-Nobelprize.org

http://www.nobelprize.org/nobel_prizes/medicine/laureates/1931/warburg-bio.html 

  • Otto Warburg effect

https://www.youtube.com/watch?v=ZVNs1aOKHw8

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