title: Proteomic identification of the lactate dehydrogenase A in a radioresistant prostate cancer xenograft mouse model for improving radiotherapy.
abstract: Radioresistance is a major challenge for prostate cancer (CaP) metastasis and recurrence after radiotherapy. This study aimed to identify potential protein markers and signaling pathways associated with radioresistance using a PC-3 radioresistant (RR) subcutaneous xenograft mouse model and verify the radiosensitization effect from a selected potential candidate. PC-3RR and PC-3 xenograft tumors were established and differential protein expression profiles from two groups of xenografts were analyzed using liquid chromatography tandem-mass spectrometry. One selected glycolysis marker, lactate dehydrogenase A (LDHA) was validated, and further investigated for its role in CaP radioresistance. We found that 378 proteins and 51 pathways were significantly differentially expressed between PC-3RR and PC-3 xenograft tumors, and that the glycolysis pathway is closely linked with CaP radioresistance. In addition, we also demonstrated that knock down of LDHA with siRNA or inhibition of LDHA activity with a LDHA specific inhibitor (FX-11), could sensitize PC-3RR cells to radiotherapy with reduced epithelial-mesenchymal transition, hypoxia, DNA repair ability and autophagy, as well as increased DNA double strand breaks and apoptosis. In summary, we identified a list of potential RR protein markers and important signaling pathways from a PC-3RR xenograft mouse model, and demonstrate that targeting LDHA combined with radiotherapy could increase radiosensitivity in RR CaP cells, suggesting that LDHA is an ideal therapeutic target to develop combination therapy for overcoming CaP radioresistance.
authors.affiliation: Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.|St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Jingli
authors.initials: J
authors.lastname: Hao
authors.affiliation: Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.|St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Graham
authors.affiliation: Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.|St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.|Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chang
authors.affiliation: Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.|St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Jie
authors.initials: J
authors.lastname: Ni
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, Sydney, NSW 2052, Australia.|School of Medical Sciences, Sydney, NSW 2052, Australia.
authors.forename: Valerie
authors.initials: V
authors.lastname: Wasinger
authors.affiliation: Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.|St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.|SEALS, Anatomical Pathology, St George Hospital, Kogarah, NSW 2217, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Beretov
authors.affiliation: Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.|St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Junli
authors.initials: J
authors.lastname: Deng
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Victoria 3217, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.affiliation: Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.|St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bucci
authors.affiliation: Department of Urology, St George Hospital, Kogarah, NSW 2217, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Malouf
authors.affiliation: Department of Urology, St George Hospital, Kogarah, NSW 2217, Australia.|Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2019, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Gillatt
authors.affiliation: Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.|St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy*; D040901:Proteomics / Q000379:methods; D011836:Radiation Tolerance; D015398:Signal Transduction
chemical_list: D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5
keywords: LDHA; glycolysis; prostate cancer; proteomics; radiotherapy