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LDH-A acetylation: implication in cancer.

Zhao D, Xiong Y, Lei QY, Guan KL - Oncotarget (2013)

View Article: PubMed Central - PubMed

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Upregulation of lactate dehydrogenase A (LDH-A) is commonly observed in many tumor types... Previous studies have revealed LDH-A transcriptional activation by the increased activity of Myc and HIF in human cancers... Moreover, the excess lactate transported out of cytoplasm may condition the microenvironment, which promotes interaction between cancer cells and stromal cells, eventually resulting in increased cancer cell migration and invasion... Recently, our group has demonstrated a mechanism of LDH-A up-regulation by post-translational modification in pancreatic cancers (Zhao, et al., Cancer Cell, 23, 464-476, 2013)... We found that LDH-A is acetylated at lysine 5 (K5) and this acetylation reduces LDH-A catalytic activity... Furthermore, acetylation decreases LDH-A protein level... Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cancer cell proliferation and migration, indicating a critical role of LDH-A acetylation in cell growth control... Importantly, K5 acetylation of LDH-A is reduced and accompanied with increased LDH-A protein levels in both early and late stages of pancreatic cancers... For most pancreatic cancer patients, they are usually diagnosed at late stages with metastasis and have limited options for treatment... The effect of chemotherapy/radiotherapy on pancreatic cancer is rather poor... LDH-A has been used to monitor treatment of some cancers since its correlation with poor prognosis and chemotherapy/radiotherapy resistance... Although we found LDH-A K5 acetylation is reduced in pancreatic cancer, we failed to detect a correlation between decreased K5 acetylation and liver cancer initiation... Further investigation to solidify the correlation between K5 acetylation of LDH-A and tumor initiation of various cancer types is needed before LDH-A K5 acetylation could be considered as a general cancer marker... Indeed, LDH-A inhibitors and siRNA inhibited tumor growth in mouse models.

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Acetylation at K5 inhibits LDH-A enzyme activity and promotes its lysosomal degradationSIRT2 deacetylates LDH-A and increases its activity and protein level. The transcription of LDH-A is stimulated by Myc and HIF in some cancer types. Glc, glucose; Pyr, pyruvate; Lac, lactate; Ac, acetylation; Mito., mitochondria.
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Figure 1: Acetylation at K5 inhibits LDH-A enzyme activity and promotes its lysosomal degradationSIRT2 deacetylates LDH-A and increases its activity and protein level. The transcription of LDH-A is stimulated by Myc and HIF in some cancer types. Glc, glucose; Pyr, pyruvate; Lac, lactate; Ac, acetylation; Mito., mitochondria.

Mentions: Reprogramming of energy metabolism, particularly the elevated glucose uptake, glycolysis and lactate production, is a hallmark of cancer. In order to support rapid cancer cell growth, glycolysis is highly elevated to provide metabolic intermediates for macromolecule biosynthesis. Instead of entering mitochondria to fuel the tricarbolic acid (TCA) cycle and oxidative phosphorylation for efficient energy production, a large fraction of pyruvate in cancer cells is converted into lactate by LDH, accompanied by NAD+ regeneration to maintain high glycolysis rate (Figure1). Moreover, the excess lactate transported out of cytoplasm may condition the microenvironment, which promotes interaction between cancer cells and stromal cells, eventually resulting in increased cancer cell migration and invasion.


LDH-A acetylation: implication in cancer.

Zhao D, Xiong Y, Lei QY, Guan KL - Oncotarget (2013)

Acetylation at K5 inhibits LDH-A enzyme activity and promotes its lysosomal degradationSIRT2 deacetylates LDH-A and increases its activity and protein level. The transcription of LDH-A is stimulated by Myc and HIF in some cancer types. Glc, glucose; Pyr, pyruvate; Lac, lactate; Ac, acetylation; Mito., mitochondria.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757233&req=5

Figure 1: Acetylation at K5 inhibits LDH-A enzyme activity and promotes its lysosomal degradationSIRT2 deacetylates LDH-A and increases its activity and protein level. The transcription of LDH-A is stimulated by Myc and HIF in some cancer types. Glc, glucose; Pyr, pyruvate; Lac, lactate; Ac, acetylation; Mito., mitochondria.
Mentions: Reprogramming of energy metabolism, particularly the elevated glucose uptake, glycolysis and lactate production, is a hallmark of cancer. In order to support rapid cancer cell growth, glycolysis is highly elevated to provide metabolic intermediates for macromolecule biosynthesis. Instead of entering mitochondria to fuel the tricarbolic acid (TCA) cycle and oxidative phosphorylation for efficient energy production, a large fraction of pyruvate in cancer cells is converted into lactate by LDH, accompanied by NAD+ regeneration to maintain high glycolysis rate (Figure1). Moreover, the excess lactate transported out of cytoplasm may condition the microenvironment, which promotes interaction between cancer cells and stromal cells, eventually resulting in increased cancer cell migration and invasion.

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Upregulation of lactate dehydrogenase A (LDH-A) is commonly observed in many tumor types... Previous studies have revealed LDH-A transcriptional activation by the increased activity of Myc and HIF in human cancers... Moreover, the excess lactate transported out of cytoplasm may condition the microenvironment, which promotes interaction between cancer cells and stromal cells, eventually resulting in increased cancer cell migration and invasion... Recently, our group has demonstrated a mechanism of LDH-A up-regulation by post-translational modification in pancreatic cancers (Zhao, et al., Cancer Cell, 23, 464-476, 2013)... We found that LDH-A is acetylated at lysine 5 (K5) and this acetylation reduces LDH-A catalytic activity... Furthermore, acetylation decreases LDH-A protein level... Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cancer cell proliferation and migration, indicating a critical role of LDH-A acetylation in cell growth control... Importantly, K5 acetylation of LDH-A is reduced and accompanied with increased LDH-A protein levels in both early and late stages of pancreatic cancers... For most pancreatic cancer patients, they are usually diagnosed at late stages with metastasis and have limited options for treatment... The effect of chemotherapy/radiotherapy on pancreatic cancer is rather poor... LDH-A has been used to monitor treatment of some cancers since its correlation with poor prognosis and chemotherapy/radiotherapy resistance... Although we found LDH-A K5 acetylation is reduced in pancreatic cancer, we failed to detect a correlation between decreased K5 acetylation and liver cancer initiation... Further investigation to solidify the correlation between K5 acetylation of LDH-A and tumor initiation of various cancer types is needed before LDH-A K5 acetylation could be considered as a general cancer marker... Indeed, LDH-A inhibitors and siRNA inhibited tumor growth in mouse models.

Show MeSH
Related in: MedlinePlus