Lactate dehydrogenase 5 isoenzyme overexpression defines resistance of prostate cancer to radiotherapy.
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.
Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
M I
MI
Koukourakis
Department of Pathology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
A
A
Giatromanolaki
Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
M
M
Panteliadou
Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
S E
SE
Pouliliou
Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
P S
PS
Chondrou
Department of Pathology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
S
S
Mavropoulou
Department of Pathology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
E
E
Sivridis
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006019:Glycolysis; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000235:genetics*
D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5