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بله
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, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.
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In the 1920s Warburg[SUP]9[/SUP] originally proposed that the increased aerobic glycolysis in cancer cells was the consequence of defects in mitochondrial respiration. Although inhibition of mitochondrial respiration may indeed be one possible reason for this,[SUP]14[/SUP] more recent theories have invoked alterations in signaling molecules and pathways as important mechanisms for aerobic glycolysis in cancer.
One line of evidence has implicated an activation and stabilization of the hypoxia inducible factor-1 (HIF-1), either as the consequence of intratumoral hypoxia or due to altered gene expression.[SUP]15[/SUP] HIF-1 then binds to hypoxia response elements in the promotor and enhancer regions of certain genes in the DNA, thereby causing overexpression of numerous proteins, including glucose transporters and glycolytic enzymes, cell survival and proliferation factors, and factors promoting angiogenesis and drug resistance.[SUP]15[/SUP] Interestingly, HIF-1 also induces the expression of pyruvate dehydrogenase (PDH)-kinase 1, which inactivates PDH, the mitochondrial enzyme that converts pyruvate to acetyl-CoA,[SUP]16[/SUP] thereby inhibiting the citrate cycle and oxidative phosphorylation. In addition, some end products of glycolysis (e.g., pyruvate) can stabilize HIF-1 and thereby promote HIF-1 inducible gene expression of vascular endothelial growth factor, EPO, GluT-3, and aldolase A.[SUP]17[/SUP]
Another, more recent line of evidence suggests that an activation of the oncogene Akt and its gene product, the serine/threonine kinase Akt, may be sufficient to stimulate the switch to aerobic glycolysis.[SUP]18[/SUP] Activation of Akt is one of first steps in the PI3K/Akt signaling pathway, which promotes cell growth, survival, and resistance to apoptosis. Activation of Akt kinase in transformed cells stimulates glucose uptake[SUP]19[/SUP] and consumption, and these cells are more susceptible than control cells to death after glucose withdrawal. Activation of the PI3K/Akt pathway causes activation of various other downstream kinases, including mammalian target of rapamycin (mTOR).[SUP]13[/SUP][SUP],[/SUP][SUP]20[/SUP] mTOR sensitizes nutrient availability within the cell and regulates cell growth and proliferation.[SUP]21[/SUP] mTOR may exert some of its effects through activation/stabilization of HIF-1.[SUP]22[/SUP] Because of the relationship between mTOR and glucose metabolism, PET imaging with FDG is under investigation for determining the treatment response to mTOR inhibitors in various malignancies, including prostate and renal cancer. Unfortunately, this process is not straightforward, because mTOR also regulates Akt through both negative and positive feedback loops.[SUP]23[/SUP] This may explain the suboptimal clinical response rates with mTOR inhibitors in some cancers with known activation of the PI3K/Akt signaling pathway. It also highlights the potential limitations of “molecular targeted therapies,†whereby inhibition of one molecule or pathway may slow down but not necessarily stop the progression of cancer, may only succeed in a subset of patients, or in some cases may even promote cancer progression.[SUP]24[/SUP]
In addition to Akt, p53 is another frequently mutated gene in cancer. p53-deficient cancer cells produce similar amounts of ATP as normal cells, but significantly higher levels of lactate, a measure of increased glycolysis. The reason is a lack of activation of the gene Synthesis of Cytochrome Oxidase-2 (SCO2), an enzyme complex that is critical during oxidative phosphorylation. This inhibition of oxygen consumption may facilitate the survival of the cancer cell in a hypoxic environment.[SUP]14[/SUP] Interestingly, in other model systems, Akt attenuates mitochondrial p53 accumulation.[SUP]25[/SUP] This is just one example of many connecting points between various cancer pathways that may affect tumor metabolism and, hence, PET imaging. Indeed, decreased expression of p53 correlates with higher incorporation of FDG into tumor cells.[SUP]26[/SUP]
Aerobic glycolysis is not only characteristic for cancer cells, but is in fact mandatory for their continued growth and survival. Although it is possible experimentally to induce a switch from aerobic glycolysis to oxidative phosphorylation in some cancer cells by inhibition of lactate dehydrogenase
source: cancer principles and practice of oncology 2008
One line of evidence has implicated an activation and stabilization of the hypoxia inducible factor-1 (HIF-1), either as the consequence of intratumoral hypoxia or due to altered gene expression.[SUP]15[/SUP] HIF-1 then binds to hypoxia response elements in the promotor and enhancer regions of certain genes in the DNA, thereby causing overexpression of numerous proteins, including glucose transporters and glycolytic enzymes, cell survival and proliferation factors, and factors promoting angiogenesis and drug resistance.[SUP]15[/SUP] Interestingly, HIF-1 also induces the expression of pyruvate dehydrogenase (PDH)-kinase 1, which inactivates PDH, the mitochondrial enzyme that converts pyruvate to acetyl-CoA,[SUP]16[/SUP] thereby inhibiting the citrate cycle and oxidative phosphorylation. In addition, some end products of glycolysis (e.g., pyruvate) can stabilize HIF-1 and thereby promote HIF-1 inducible gene expression of vascular endothelial growth factor, EPO, GluT-3, and aldolase A.[SUP]17[/SUP]
Another, more recent line of evidence suggests that an activation of the oncogene Akt and its gene product, the serine/threonine kinase Akt, may be sufficient to stimulate the switch to aerobic glycolysis.[SUP]18[/SUP] Activation of Akt is one of first steps in the PI3K/Akt signaling pathway, which promotes cell growth, survival, and resistance to apoptosis. Activation of Akt kinase in transformed cells stimulates glucose uptake[SUP]19[/SUP] and consumption, and these cells are more susceptible than control cells to death after glucose withdrawal. Activation of the PI3K/Akt pathway causes activation of various other downstream kinases, including mammalian target of rapamycin (mTOR).[SUP]13[/SUP][SUP],[/SUP][SUP]20[/SUP] mTOR sensitizes nutrient availability within the cell and regulates cell growth and proliferation.[SUP]21[/SUP] mTOR may exert some of its effects through activation/stabilization of HIF-1.[SUP]22[/SUP] Because of the relationship between mTOR and glucose metabolism, PET imaging with FDG is under investigation for determining the treatment response to mTOR inhibitors in various malignancies, including prostate and renal cancer. Unfortunately, this process is not straightforward, because mTOR also regulates Akt through both negative and positive feedback loops.[SUP]23[/SUP] This may explain the suboptimal clinical response rates with mTOR inhibitors in some cancers with known activation of the PI3K/Akt signaling pathway. It also highlights the potential limitations of “molecular targeted therapies,†whereby inhibition of one molecule or pathway may slow down but not necessarily stop the progression of cancer, may only succeed in a subset of patients, or in some cases may even promote cancer progression.[SUP]24[/SUP]
In addition to Akt, p53 is another frequently mutated gene in cancer. p53-deficient cancer cells produce similar amounts of ATP as normal cells, but significantly higher levels of lactate, a measure of increased glycolysis. The reason is a lack of activation of the gene Synthesis of Cytochrome Oxidase-2 (SCO2), an enzyme complex that is critical during oxidative phosphorylation. This inhibition of oxygen consumption may facilitate the survival of the cancer cell in a hypoxic environment.[SUP]14[/SUP] Interestingly, in other model systems, Akt attenuates mitochondrial p53 accumulation.[SUP]25[/SUP] This is just one example of many connecting points between various cancer pathways that may affect tumor metabolism and, hence, PET imaging. Indeed, decreased expression of p53 correlates with higher incorporation of FDG into tumor cells.[SUP]26[/SUP]
Aerobic glycolysis is not only characteristic for cancer cells, but is in fact mandatory for their continued growth and survival. Although it is possible experimentally to induce a switch from aerobic glycolysis to oxidative phosphorylation in some cancer cells by inhibition of lactate dehydrogenase
source: cancer principles and practice of oncology 2008
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