Lactate Dehydrogenase 5 Expression Research Articles

Investigation of the relationship between betatrophin and certain key enzymes involved in carbohydrate and lipid metabolism in insulin-resistant mice.

The present study sought to examine the relationship of betatrophin with certain key enzymes, namely lactate dehydrogenase-5 (LDH5), citrate synthase (CS), and acetyl-CoA carboxylase-1 (ACC1), in insulin-resistant mice. Eight-week-old male C57BL6/J mice were used in this study (experimental group n=10 and control group n=10). S961 was administered using an osmotic pump to induce insulin resistance in the mice. The betatrophin, LDH5, CS, and ACC1 expression levels were determined from the livers of the mice using the real-time polymerase chain reaction (RT-PCR) method. Moreover, biochemical parameters such as the serum betatrophin, fasting glucose, insulin, triglyceride, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels were analyzed. The betatrophin expression and serum betatrophin (p=0.000), fasting glucose, insulin, triglyceride (p≤0.001), and total cholesterol (p=0.013) levels were increased in the experimental group. In addition, the CS gene expression level was statistically significantly decreased in the experimental group (p=0.01). Although strong correlation was found between the expression and serum betatrophin and triglyceride levels, no correlation was found between the betatrophin gene expression and the LDH5, ACC1, and CS gene expression levels. The betatrophin level appears to play an important role in the regulation of triglyceride metabolism, while insulin resistance increases both the betatrophin gene expression and serum levels and decreases the CS expression level. The findings suggest that betatrophin may not regulate carbohydrate metabolism through CS and LDH5 or lipid metabolism directly through the ACC1 enzyme.

Prognostic significance of lactate dehydrogenase-5 expression in patients with prostate cancer treated with androgen deprivation therapy and androgen receptor axis-targeted agents.

300 Background: Evidence suggests that hypoxic zones are prevalent in prostate cancer (PC). Recent clinical data showed that the expression of lactate dehydrogenase-5 (LDH5), a tumor hypoxia marker, affected the outcome of PC treated with radiation therapy. However, the impact of its expression on hormone therapy remains unclear. We investigated the predictive value of LDH5 expression in biopsy specimens from patients with PC treated with hormone therapy. Methods: Baseline data were available from 50 patients with PC treated with both androgen deprivation therapy (ADT) and novel androgen receptor axis-targeted agents (ARATs). LDH5 expression in the biopsy specimens was analyzed using immunohistochemical staining. Patients were stratified according to LDH5 expression in needle biopsy specimens. The relationships between LDH5 expression and baseline data at diagnosis, time to emergence of castration resistance, prostate-specific antigen (PSA) progression, and overall survival from induction of ADT and ARATs were examined. Results: Biopsy specimens from 19 patients highly expressed LDH5. High LDH5 expression was significantly associated with high Gleason scores (≥8) (p = 0.03), high clinical T stage (p = 0.008), and the likelihood of having at least one lymph node (p = 0.019) and metastatic lesion (p = 0.024). In a multivariate logistic regression model, LDH5 expression was significantly associated with high clinical T stage (p = 0.038), the presence of lymph node metastasis (p = 0.013), and high neutrophil-to-lymphocyte ratio (p = 0.016). Multivariate Cox regression analysis showed that high LDH5 expression was a significant predictor of time to emergence of castration resistance (hazard ratio [HR] 2.45, 95% confidence interval [CI] 1.12–5.36, p = 0.025) and overall survival (HR 9.3, 95% CI 2.17–39.8, p = 0.003). No significant association was observed between LDH5 expression and time to PSA progression from the induction of ARATs in univariate Cox regression analysis (p = 0.28). Conclusions: The results of this study suggest that LDH5 expression is a predictor of treatment outcomes in patients with PC treated with ADT.

Phosphohistone 3 (PHH3) and lactate dehydrogenase 5 (LDH5) are expressed in ductal carcinoma in situ of the breast: possible clinical implications

Purpose: Proliferation and pre-malignancy are typical features of DCIS. The expression of PHH3 as a marker for proliferation and LDH 5 as an indicator for oxygen independent energy metabolism was investigated in order to assess their potential for an improved characterisation of these lesions. Methods: Archived tissue blocks and clinical records of 130 patients with DCIS. Immunohistochemistry for PHH3, LDH5, estrogen receptor (ER), progesterone receptor (PR), human EGF receptor 2 (HER2). Silverstein nuclear grading. Chi Square test for all factors. Results: Percentage of positive patients was 69% for PHH3, 94% for LDH5, 76% for ER, 67% for PR, and 21% for HER2. Significant correlation was seen between PHH3 and LDH5 expression. No correlation could be found for any of the other comparisons. Conclusion: This is the first description of PHH3 and LDH5 in DCIS. The biological significance of PHH3 remains to be determined in a larger set of patients. LDH5 may be a useful diagnostic marker in the future. Positive HER2 receptors were considerably less frequent than previously reported.

Hypoxia-inducible proteins HIF1α and lactate dehydrogenase LDH5, key markers of anaerobic metabolism, relate with stem cell markers and poor post-radiotherapy outcome in bladder cancer

Purpose: To assess whether anaerobic metabolism, proliferation activity and stem cell content are linked with radioresistance in bladder cancer. Materials and methods: Tissue sections from 66 patients with invasive transitional cell bladder cancer treated with hypofractionated accelerated radiotherapy, was immunohistochemically analyzed for the Hypoxia-Inducible Factor 1α (HIF1α) and the anaerobic glycolysis enzyme lactate dehydrogenase 5 (LDH5). Proliferation index (Ki-67) and stem-cell marker (cluster of differentiation CD44, aldehyde dehydrogenase ALDH1) expression was also examined. Results: Both HIF1α and LDH5 expression were linked with high CD44 stem cell population (p = 0.001 and 0.05, respectively), while high Ki-67 proliferation index was linked with nuclear LDH5 expression (p = 0.03) and high histological grade (p = 0.02). A strong significant association of HIF1α (p = 0.0009) and of LDH5 (p < 0.0001) with poor local relapse free survival (LRFS) was noted, which was also confirmed in multivariate analysis. A significant association with overall survival was also noted. Silencing of lactate dehydrogenase LDHA gene in the human RT112 bladder cancer cell line, or exposure to oxamate (LDH activity inhibitor), resulted in strong radio-sensitization. Conclusions: HIF1α and LDH5 are markers of poor outcome in patients with bladder cancer treated with radiotherapy. Blockage of anaerobic metabolism may prove of importance in clinical radiotherapy.

Equating salivary lactate dehydrogenase (LDH) with LDH-5 expression in patients with oral squamous cell carcinoma: An insight into metabolic reprogramming of cancer cell as a predictor of aggressive phenotype.

Oral squamous cell carcinoma (OSCC) is the sixth most common human malignancy. According to World Health Organization, oral cancer has been reported to have the highest morbidity and mortality and a survival rate of approximately 50% at 5years from diagnosis. This is attributed to the subjectivity in TNM staging and histological grading which may result in less than optimum treatment outcomes including tumour recurrence. One of the hallmarks of cancer is aerobic glycolysis also known as the Warburg effect. This glycolytic phenotype (hypoxic state) not only confers immortality to cancer cells, but also correlates with the belligerent behaviour of various malignancies and is reflected as an increase in the expression of lactate dehydrogenase 5 (LDH-5), the main isoform of LDH catalysing the conversion of pyruvate to lactate during glycolysis. The diagnostic role of salivary LDH in assessing the metabolic phenotype of oral cancer has not been studied. Since salivary LDH is mainly sourced from oral epithelial cells, any pathological changes in the epithelium should reflect diagnostically in saliva. Thus in our current research, we made an attempt to ascertain the biological behaviour and aggressiveness of OSCC by appraising its metabolic phenotype as indirectly reflected in salivary LDH activity. We found that salivary LDH can be used to assess the aggressiveness of different histological grades of OSCC. For the first time, an evidence of differing metabolic behaviour in similar histologic tumour grade is presented. Taken together, our study examines the inclusion of salivary LDH as potential diagnostic parameter and therapeutic index in OSCC.

Overexpression of metabolic markers PKM2 and LDH5 correlates with aggressive clinicopathological features and adverse patient prognosis in tongue cancer.

Pyruvate kinase M2 (PKM2) and lactate dehydrogenase 5 (LDH5) are two metabolic and oncogenic markers of cancer. In this study, we sought to investigate their expression patterns and prognostic value in tongue squamous cell carcinoma (TSCC). The expression and subcellular localization of PKM2 and LDH5 in TSCC cell lines were determined by Western blot and immunofluorescence. PKM2 and LDH5 abundance was examined by immunohistochemistry in 63 TSCC tumour specimens; their association with multiple clinicopathological parameters and overall patient survival was assessed. The protein levels of PKM2 and LDH5 were both significantly higher in TSCC cells than in an immortalized oral epithelial cell line. Overexpression of PKM2 associated significantly with cervical node metastasis (P=0.0373), while elevated LDH5 levels correlated significantly with tumour size (P=0.0094), pathological grade (P=0.0052), cervical node metastasis (P=0.0023) and clinical stage (P=0.0024). Patients with tumours showing an increase in either PKM2 or LDH5 expression displayed significantly reduced overall survival, while patients with tumours overexpressing both proteins showed the worst prognosis with lowest overall survival. Furthermore, PKM2 and LDH5 were identified as independent prognostic predictors for overall patient survival in TSCC. Our data indicate that overexpression of PKM2 and LDH5 associates with key clinicopathological features and unfavourable prognosis in TSCC.

LDH5 overexpression is associated with poor survival in patients with solid tumors: a meta-analysis.

Lactate dehydrogenase 5 (LDH5) is believed to be particularly important and a reliable marker of malignancy. However, it is still controversial whether LDH5 expression can be regarded as a prognostic factor for cancer patients. We reviewed the literature by performing an electronic database search via PubMed to identify eligible studies that assessed the impact of LDH5 as a cancer prognostic marker and its association with HIF-1α. Heterogeneity and publication bias were also assessed. A total of 12 literatures which included 1,892 cancer patients were combined in the final analysis. Meta-analysis revealed that LDH5 overexpression was associated with an unfavorable overall survival (12 studies, 1,597 patients; HR 1.59, 95 % CI 1.17-2.16) and disease/recurrence/progression-free survival (7 studies; 1,086 patients; HR 1.46, 95 % CI 1.04-2.04) among solid tumor patients. Meta-analysis revealed an association between the expression of LDH5 and hypoxia-inducible factors 1 (OR 2.72, 95 % CI 1.66-4.45). Publication bias could not be excluded when investigating the association of LDH5 expression and overall survival. However, when we accounted for publication bias using the trim and fill method, the results remained significant (HR 1.435, 95 % CI 1.071-1.923, P < 0.05) suggesting the stability of our results. Therefore, our study suggested that LDH5 overexpression had a poor prognosis value in cancer patients. The results of this meta-analysis suggest that high LDH5 expression is associated with HIF-1α and poor overall survival in cancer patients.

High Lactate Dehydrogenase 5 Expression Correlates with High Tumoral and Stromal Vascular Endothelial Growth Factor Expression in Gastric Cancer

Background: Lactate dehydrogenase 5 (LDH5) is a major lactate dehydrogenase isoenzyme catalyzing the transformation of pyruvate to lactate to provide anaerobic energy. Vascular endothelial growth factor (VEGF) is expressed in both tumor and stromal cells in gastric cancer. Our aim was to study the prognostic effect of LDH5, and tumoral and stromal expression of the angiogenic factor VEGF in gastric cancer, and the intercorrelation of tissue expression of both factors. Methods: Tissue microarray analysis of 382 consecutive gastric cancer resection specimens was used for immunohistochemistry of LDH5 and VEGF, and expression of LDH5, tumoral VEGF, and stromal VEGF was categorized into low and high groups. Results: High expression was observed for LDH5 in 57.9% (219/378), tumoral VEGF in 35.7% (136/381), and stromal VEGF in 58.5% (223/381) of the specimens. Regarding high expression of LDH5 and VEGF, significant associations with intestinal type, advanced gastric cancer, lymph node metastasis, higher TNM stage, and upper-third location were noted. Positive intercorrelations occurred among the expression of LDH5 and VEGF. Results of survival analyses revealed a significant association of high expression of LDH5 and VEGF with lower survival (overall and disease-free survival). Five-year survival rates were significantly lower in tumors with high LDH5 and tumoral VEGF expression in diffuse- or mixed-type cancers and high expression of stromal VEGF in intestinal-type cancer. Conclusion: The results of our study showed that high LDH5 and VEGF expression in both tumor and stroma was a prognostic factor for patients with gastric cancers, especially diffuse- or mixed-type cancers. Therefore, LDH5 expression may play a role in the regulation of tumoral and stromal VEGF expression in gastric cancer. Our results suggest the potential use of LDH5 expression as a biomarker for response to VEGF-targeted therapy.

Autophagy proteins in prostate cancer: Relation with anaerobic metabolism and Gleason score

ObjectivesUp-regulation of autophagy provides an important survival mechanism to normal and malignant cells residing in a hypoxic and unfavorable nutritional environment. Yet, its role in the biology of prostate cancer remains poorly understood. MethodsIn this study we investigated the expression of four major autophagy proteins, namely the microtubule-associated protein 1 light chain 3A (LC3A), LC3B, Beclin 1, and p62, together with an enzyme of anaerobic metabolism, the lactate dehydrogenase 5 (LDH5), in relation to Gleason score and extraprostatic invasion. A series of 96 prostate adenocarcinomas was examined using immunohistochemical techniques and appropriate antibodies. ResultsThe LC3A protein was expressed in the form of “stone-like” structures, and diffuse cytoplasmic staining, the LC3B reactivity was solely cytoplasmic, whereas that of p62 and LDH5 was both cytoplasmic and nuclear. A median count of 0.90 “stone-like” structures per 200×optical field (range 0–3.6) was highly associated with a high Gleason score. Similarly, a strong cytoplasmic LC3A, LC3B, and p62 expression, when extensive (present in>50% tumor cells per section), was significantly associated with LDH5 and a high Gleason score. In addition, extensive cytoplasmic p62 expression was related with LC3A and B reactivity and also with extraprostatic invasion. Extensive Beclin-1 expression was significantly linked with extraprostatic invasion and also with p62 and LDH5 expression. ConclusionsImmunohistochemical detection of autophagy proteins may potentially prove to be useful as prognostic markers and a tool for the stratification of patients in therapeutic trials targeting autophagy in prostate cancer.

Increased LDH5 expression is associated with lymph node metastasis and outcome in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) account for more than 90% of all oral malignant lesions. Lactate dehydrogenase 5 (LDH5) has the highest efficiency among all other isoenzymes to catalyse pyruvate transformation to lactate and is significantly overexpressed in several different tumour entities. LDH5 overexpression confers an advantage on malignant cells, allows them to grow faster, and to metastasize. No data regarding LDH5 expression and OSCC outcome are available. Expression of LDH5 was analysed in OSCC specimen (n=191) and cancer cell lines (BICR3, BICR56) by immunohistochemistry, real-time quantitative reverse transcription-PCR (RT-PCR) analysis, and western blotting. Scanned images were digitally analysed using ImageJ and the immunomembrane plug-in. LDH5 expression on protein level was correlated with clinicopathological characteristics and impact on survival. LDH5 was co-labelled with glucose transporter-1 (GLUT-1), Ki-67, and hypoxia inducible factor 1 (HIF-1α) in immunohistochemical double staining experiments. Expression subgroups were identified by receiver operating characteristics analysis. LDH5 expression was significantly associated with tumour progression, and recurrence of the tumour. Multivariate analysis demonstrated LDH5 expression as an independent prognostic factor (p<0.0001). Immunohistochemical double staining experiments revealed LDH5 expression by cancer cells in association with glucose uptake (GLUT-1), proliferation (Ki-67), and hypoxia (HIF-1α). LDH5 specificity was confirmed by western blot and RT-PCR analysis. For the first time, this study provides evidence that LDH5 expression in OSCC might be associated with tumour formation and metastasis in a large patient cohort. Therefore, adjuvant therapies targeting glucose metabolism might be promising for therapy of OSCC.

Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-β

Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-β activation in vitro. Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; α-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-β. TGF-β induced expression of LDH5 via hypoxia-inducible factor 1α (HIF1α). Importantly, overexpression of both HIF1α and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-β to induce differentiation. Furthermore, inhibition of both HIF1α and LDH5 inhibited TGF-β-induced myofibroblast differentiation. We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-β. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.

Lactate Dehydrogenase-5 (LDH-5) Expression in Human Gastric Cancer: Association with Hypoxia-Inducible Factor (HIF-1α) Pathway, Angiogenic Factors Production and Poor Prognosis

Lactate-dehydrogenase-5 (LDH-5) is an important isoenzyme converting pyruvate to lactate under hypoxic conditions and might play an important role in the development and progression of malignancies. However, the role of LDH-5 in gastric cancer is still unclear. In this study, we investigated the clinical significance of LDH-5 expression in gastric carcinoma. LDH-5 expression in 152 patients with different grade and stage gastric carcinoma was analyzed by immunohistochemistry. In addition, hypoxia-inducible factor 1alpha (HIF-1alpha) as a marker of tumor hypoxia, as well as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) as angiogenesis parameters were also assessed in this study. Correlations between the expression of investigated proteins and various clinicopathological factors including survival were determined. There were 94 cases (61.8%) showing high LDH-5 expression, and 95 patients (62.5%) had high HIF-1alpha expression. Positive correlation was found between LDH-5 expression and HIF-1alpha, VEGF, and COX-2. The overexpression of LDH-5 was more prevalent in advanced tumors having positive vessel invasion. Patients with overexpression of LDH-5 showed far lower disease-free (63.5% vs 82.7%) and overall (56.3% vs 78.4%) survival rates compared with patients with low LDH-5 expression. HIF-1alpha expression was shown to have no significance on survival. In multivariate analysis, high LDH-5 expression kept its independence as a negative prognostic indicator. The results of the current study show that LDH-5 expression may be a useful prognostic factor for patients with gastric carcinoma.

Lactate dehydrogenase 5 expression in non-Hodgkin B-cell lymphomas is associated with hypoxia regulated proteins

The expression of lactate dehydrogenase 5 (LDH5), the major LDH isoenzyme sustaining the anaerobic transformation glycolysis was examined in B-cell non-Hodgkin lymphomas. Multi-tissue slides obtained from patients with diffuse large B-cell lymphomas (DLBCL; 95 cases), follicular lymphomas (FL; 49 cases) and from non-neoplastic lymph nodes (48 cases) were used for immuhistochemical analysis. High LDH5 expression (cytoplasmic and nuclear) was noted in 79/95 and 29/49 cases of DLBCL and FL, respectively (p = 0.002). No expression was noted in non-neoplastic lymphocytes. In DLBCL, LDH5 expression was significantly related to hypoxia inducible factor HIF1α, HIF2α, vascular endothelial growth factor (VEGF) and phosphorylated vascular endothelial growth factor receptor 2 (VEGFR2/KDR) expression. In FL, however, a significant relation was confirmed with pVEGFR2/KDR and HIF2α. FL cases with the highest microvessel density were those, which lacked both LDH5 and VEGF expression. It is concluded that LDH5 is highly upregulated in B-cell non-Hodgkin lymphomas and is in direct relation to HIFs expression. LDH5 expression is linked with activated VEGFR2/KDR expression in both lymphoid lesions.

Lactate Dehydrogenase 5 Expression in Operable Colorectal Cancer: Strong Association With Survival and Activated Vascular Endothelial Growth Factor Pathway—A Report of the Tumour Angiogenesis Research Group

Lactate dehydrogenase 5 (LDH-5) regulates, under hypoxic conditions, the anaerobic transformation of pyruvate to lactate for energy acquisition. Several studies have shown that serum LDH may be an ominous prognostic marker in malignant tumors. The clinical significance of tissue LDH-5, however, remains largely unexplored. We investigated the immunohistochemical expression of LDH-5 in a series of 128 stage II/III colorectal adenocarcinomas treated with surgery alone. In addition, markers of tumor hypoxia (hypoxia-inducible factor 1 alpha [HIF1alpha]), angiogenesis (vascular endothelial growth factor [VEGF] and phosporylated kinase domain receptor [pKDR]/flk-1 receptor) and the tumor vascular density (CD31 positive standard vascular density [sVD] and pKDR positive activated vascular density [aVD]) were assessed. The expression of LDH-5, together with that of HIF1alpha and pKDR, was both nuclear and cytoplasmic. Assessment, with minimal interobserver variability, was achieved using a previously described scoring system. LDH-5 was significantly associated with HIF1alpha (P = .01), aVD (P = .001) and, particularly, with pKDR expression in cancer cells (P = .0001). Tissue LDH-5 expression was linked with elevated serum LDH levels, but serum levels failed to reflect tissue expression in 71% of LDH-5 positive cases. In univariate analysis tissue LDH-5 was associated with poor survival (P = .0003, HR 15.1), whereas in multivariate analysis this isoenzyme was the strongest independent prognostic factor (P = .0009). VEGF, pKDR, aVD, sVD and vascular invasion were all significantly related to unfavorable prognosis. The immunohistochemical assessment of tissue LDH-5 and pKDR provides important prognostic information in operable colorectal cancer. The strong association between LDH-5 and pKDR expression would justify their use as surrogate markers to screen patients for tyrosine kinase inhibitor therapy.

Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis

Purpose. Lactate dehydrogenase (LDH-5) is a major lactate dehydrogenase isoenzyme catalyzing the transformation of pyruvate to lactate for anaerobic acquisition energy. In this study, the expression of LDH-5 was assessed in the normal and malignant endometrium. Its role in prognosis and tumor angiogenesis and hypoxia was also examined. Experimental design. Tissue specimens from 68 patients with clinical stage I endometrial adenocarcinoma of the endometrioid cell type and 20 samples from normally cycling endometrium were investigated immunohistochemically for the expression of LDH-5. The vascular density and the expression of angiogenesis/hypoxia-related proteins (VEGF, HIF1α, HIF2α, phosphorylated VEGFR2/KDR, VEGF/KDR complex) were also assessed. Results. Unlike other normal epithelia, the glandular endometrial cells consistently expressed LDH-5 suggesting a role of this enzyme in the normal menstrual cycle. Endometrial adenocarcinomas displayed LDH-5 expression in 31/68 (45.5%) cases with those having a high LDH-5 expression being connected with a low lymphocytic response; this may suggest an important role of LDH-5 and, presumably, lactate release in tumor escape from host immuno-surveillance. More importantly, LDH-5 was significantly associated with the expression of phosphorylated VEGFR2/KDR receptors in cancer cells and tumor-associated vasculature. LDH-5 was one of the most powerful and independent prognostic variables. Conclusions. LDH-5 expression is an independent prognostic marker in endometrial cancer, linked with impaired host immune response and activation of VEGFR2/KDR receptors in both cancer cells and tumor-associated vasculature. Adjuvant radio-chemotherapy may, therefore, be useful in these cases, while the administration of VEGF- tyrosine kinase receptor inhibitors emerges as a therapeutic option.