Press-pulse: a novel therapeutic strategy for the metabolic management of cancer 癌症代謝管理的新治療策略

中文版谷歌中文翻譯(90% 準確率) | English translation
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Contact Dr. Lu for information about cancer treatments。聯繫盧博士,獲取有關癌症治療資訊。

The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible [2, 31, 32, 36,58, 59]. Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen [31, 32,36, 58, 59]. Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells [60]. Although Warburg insisted that aerobic glycolysis confuses the issue of insufficient respiration as the origin of cancer [31, 32], some in the cancer metabolism field have persisted in thinking that aerobic glycolysis (Warburg effect) is a central issue in cancer metabolism [39, 61]. Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration [36]. Hence, the targeting of fermentable fuels becomes of prime importance for cancer management.

Substantial evidence exists showing that many cancers avidly consume glucose and produce lactic acid [62, 63, 64, 65, 66, 67]. The diagnostic procedure of 18F-deoxyglucose positron emission tomography (FDG-PET) is considered evidence for the elevated use of glucose by some tumors [66]. Elevated glucose consumption would be expected for any glucose-dependent cell with quantitative or qualitative abnormalities in mitochondria, as enhanced fermentation would be needed to compensate for the insufficient respiration [43, 68]. Indeed, all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin, the signature lipid of the inner mitochondrial membrane that regulates oxidative phosphorylation [69, 70, 71, 72, 73, 74]. Mammalian cells containing abnormalities in cardiolipin cannot respire effectively and will therefore need to increase energy production through fermentation reactions [41, 70, 73, 75, 76, 77, 78]. This fact cannot be overemphasized considering arguments that tumor cells can have normal respiration [39, 61, 79]. The expression of immature cardiolipin linked to reduced Complex I activity in the inner mitochondrial membrane of tumorigenic and non-tumorigenic cells suggests that many proliferative cells grown in culture obtain energy through fermentation rather than through oxidative phosphorylation despite the appearance of normal oxygen consumption [41, 43]. The cardiolipin abnormalities found in tumor cells provide direct support for Warburg’s central theory. In addition to cardiolipin abnormalities, Pedersen also showed that some degree of abnormality could be found in the number, structure, or function of tumor cell mitochondria providing further support for Warburg’s theory [68]. The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming [2, 36, 53, 80, 81, 82, 83, 84, 85]. Hence, respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.

Although the abnormal energy metabolism and mitochondrial abnormalities seen in most cancers could arise in part through oncogenic modulation of metabolism [4, 39, 86], the data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis [2, 14, 24, 87, 88]. Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis [14, 87]. The results from these experiments must be viewed together, as results from any given single experiment are not capable of overturning the gene theory [14]. Recent advances in CRISPR/Cas9 technology might help to generate nuclei with changes in specific tumor-associated genes to further evaluate the influence of gene mutations and mitochondrial function on tumorigenesis. The acquisition of dysfunctional mitochondria in macrophages through fusion hybridization with non-metastatic tumor cells provides a compelling argument for the origin of those cancer cells that become metastatic [5, 89,90, 91]. We recently showed how all of the Hanahan & Weinberg hallmarks of cancer, including the genomic mutations, could be linked either directly or indirectly to mitochondrial dysfunction [2, 56,92].

Amino acid fermentation could also drive cancer metabolism

As the result of insufficient aerobic respiration, cancer cells must rely primarily on fermentation metabolism to maintain energy balance and viability. Besides substrate level phosphorylation in the cytoplasm through lactic acid fermentation, TCA cycle substrate level phosphorylation can also produce significant amounts ATP [93, 94, 95, 96, 97, 98]. In addition to glucose, cancer cells also rely heavily on glutamine for growth and survival [99, 100, 101, 102]. Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle. In addition to serving as a carbon/nitrogen source for tumor cell growth, glutamine also plays a role in cancer cell survival and growth through enzymatic release of ammonia into the microenvironment [103]. The TCA cycle succinate thiokinase reaction could generate the majority of cellular ATP through substrate level phosphorylation under hypoxia or in tumor cells with defective oxidative phosphorylation [78]. Mitochondrial ATP production through TCA cycle substrate level phosphorylation, using glutamine as a substrate, could give the appearance that mitochondrial energy metabolism is normal in some cancer cells especially in combination with oxygen consumption and CO2 production. Although Warburg did not address the role of TCA cycle substrate level phosphorylation in his original work [31, 36], an increase in TCA cycle substrate level phosphorylation would be expected in cells with OxPhos deficiencies, just as lactic acid fermentation is expected in cells with this deficiency. Further studies will be needed to substantiate the role of glutamine fermentation in cancer cells.

Glucose and glutamine act synergistically for driving rapid tumor cell growth. Glutamine metabolism can produce ATP from the TCA cycle under aerobic conditions. Glutamine is also a nitrogen donor for nucleotide biosynthesis and can serve as precursor for lipid synthesis under hypoxic conditions [104, 105]. We also found that only minor amounts of glutamine are metabolized to lactic acid under either normoxia or hypoxia in the VM-M3 invasive glioblastoma cells consistent with findings in other tumor cells [105, 106, 107]. We suggest that the metabolism of glucose and glutamine for energy will depend on the physiological state of the tumor microenvironment, and will be of greater significance in tumors with an aggressive Warburg phenotype. We found that glutamine targeting can be effective in managing systemic metastatic cancer in the VM/Dk mice [108].

Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions [94, 96, 97, 109, 110]. Succinate is a waste product of amino acid fermentation that can enhance inflammation as well as inhibit a family of prolyl hydroxylases, which facilitate Hif-1α degradation through the von Hippel–Lindau (VHL) gene product [111, 112, 113]. Through its action on several glycolytic pathways, Hif-1α stabilization enhances aerobic fermentation [114, 115, 116]. It can be difficult to determine, however, the degree to which mitochondrial ATP production in tumor cells arises from coupled respiration or from TCA cycle substrate level phosphorylation [94, 98].

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