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Lactate dehydrogenase 5 isoenzyme overexpression defines resistance of prostate cancer to radiotherapy.

ABSTRACT: BACKGROUND: Radiotherapy provides high-cure rates in prostate cancer. Despite its overall slow clinical growth, high proliferation rates documented in a subset of tumours relate to poor radiotherapy outcome. This study examines the role of anaerobic metabolism in prostate cancer growth and resistance to radiotherapy. METHODS: Biopsy samples from 83 patients with prostate cancer undergoing radical hypofractionated and accelerated radiotherapy were analysed for MIB1 proliferation index and for lactate dehydrogenase isoenzyme LDH5, a marker of tumour anaerobic metabolism. Ninety-five surgical samples were in parallel analysed. Correlation with histopathological variables, PSA and radiotherapy outcome was assessed. Dose-response experiments were performed in PC3 and DU145 cancer cell lines. RESULTS: High MIB1 index (noted in 25% of cases) was directly related to Gleason score (P<0.0001), T3-stage (P=0.0008) and PSA levels (P=0.03). High LDH5 (noted in 65% of cases) was directly related to MIB1 index (P<0.0001), Gleason score (P=0.02) and T3-stage (P=0.001). High Gleason score, MIB1, LDH5 and PSA levels were significantly related to poor BRFS (P=0.007, 0.01, 0.03 and 0.01, respectively). High Gleason score (P=0.04), LDH5 (P=0.01) and PSA levels (P=0.003) were significantly related to local recurrence. MIB1 and T-stage did not affect local control. Silencing of LDHA gene in both prostate cancer cell lines resulted in significant radiosensitisation. CONCLUSIONS: LDH5 overexpression is significantly linked to highly proliferating prostate carcinomas and with biochemical failure and local relapse following radiotherapy. Hypoxia and LDHA targeting agents may prove useful to overcome radioresistance in a subgroup of prostate carcinomas with anaerobic metabolic predilection.

SUBMITTER: Koukourakis MI

PROVIDER: S-EPMC4007238 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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Project description:Testis-specific lactate dehydrogenase (LDH-C₄) is one of the lactate dehydrogenase (LDH) isozymes that catalyze the terminal reaction of pyruvate to lactate in the glycolytic pathway. LDH-C₄ in mammals was previously thought to be expressed only in spermatozoa and testis and not in other tissues. Plateau pika (Ochotona curzoniae) belongs to the genus Ochotona of the Ochotonidea family. It is a hypoxia-tolerant species living in remote mountain areas at altitudes of 3000-5000 m above sea level on the Qinghai-Tibet Plateau. Surprisingly, Ldh-c is expressed not only in its testis and sperm, but also in somatic tissues of plateau pika. To shed light on the function of LDH-C₄ in somatic cells, Ldh-a, Ldh-b, and Ldh-c of plateau pika were subcloned into bacterial expression vectors. The pure enzymes of Lactate Dehydrogenase A₄ (LDH-A₄), Lactate Dehydrogenase B₄ (LDH-B₄), and LDH-C₄ were prepared by a series of expression and purification processes, and the three enzymes were identified by the method of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and native polyacrylamide gel electrophoresis (PAGE). The enzymatic kinetics properties of these enzymes were studied by Lineweaver-Burk double-reciprocal plots. The results showed the Michaelis constant (Km) of LDH-C₄ for pyruvate and lactate was 0.052 and 4.934 mmol/L, respectively, with an approximate 90 times higher affinity of LDH-C₄ for pyruvate than for lactate. At relatively high concentrations of lactate, the inhibition constant (Ki) of the LDH isoenzymes varied: LDH-A₄ (Ki = 26.900 mmol/L), LDH-B₄ (Ki = 23.800 mmol/L), and LDH-C₄ (Ki = 65.500 mmol/L). These data suggest that inhibition of lactate by LDH-A₄ and LDH-B₄ were stronger than LDH-C₄. In light of the enzymatic kinetics properties, we suggest that the plateau pika can reduce reliance on oxygen supply and enhance its adaptation to the hypoxic environments due to increased anaerobic glycolysis by LDH-C₄.

Project description:Background: This present study aimed to explore the prognostic value of pretreatment neutrophil and lactate dehydrogenase (LDH) and to develop a prognostic risk scoring model to predict prognosis in esophageal squamous cell cancer (ESCC) patients treated with definitive radiotherapy. Methods: Retrospectively collected data of patients who received definitive radiotherapy for ESCC at Shantou Central Hospital between January 2009 and December 2015 were included for the analysis. The association between the level of LDH and neutrophil and clinicopathological characteristics were analyzed. We performed univariate and multivariate analyses to identify the prognostic predictors for patients with ESCC. Based on the results, we also developed a prognostic risk scoring model and assessed its predictive ability in the subgroups. Results: A total of 567 patients who received definitive radiotherapy for ESCC were included in the present study. The optimal cutoff values were 4.5 × 109/L, 3.25, and 220 U/L for neutrophil, neutrophil-to-lymphocyte ratio (NLR), and LDH, respectively. A high level of LDH was significantly associated with advanced N stage (p = 0.031), and neutrophil count was significantly associated with gender (p = 0.001), T stage (p < 0.001), N stage (p = 0.019), clinical stage (p < 0.001), and NLR (p < 0.001). Multivariate survival analysis identified gender (p = 0.006), T stage (p < 0.001), N stage (p = 0.008), treatment modality (p < 0.001), LDH level (p = 0.012), and neutrophil count (p = 0.038) as independent prognostic factors for overall survival. Furthermore, a new prognostic risk scoring (PRS) model based on six prognostic factors was developed, in which the patients were divided into three groups with distinct prognosis (?2 = 67.94, p < 0.0001). Conclusions: Elevated baseline LDH level and neutrophil count predicted poor prognosis for ESCC patients treated with definitive radiotherapy. A PRS model comprised of LDH, neutrophil count, and other prognostic factors would help identify the patients who would benefit the most from definitive radiotherapy.

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Lactate dehydrogenase 5 isoenzyme overexpression defines resistance of prostate cancer to radiotherapy.

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