Proteomic identification of the lactate dehydrogenase A in a radioresistant prostate cancer xenograft mouse model for improving radiotherapy
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Jingli Hao1,2, Peter Graham1,2, Lei Chang1,2,3, Jie Ni1,2, Valerie Wasinger4,5, Julia Beretov1,2,6, Junli Deng1,2, Wei Duan7, Joseph Bucci1,2, David Malouf8, David Gillatt8,9, Yong Li1,2
1Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia
2St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
3Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
4Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, Sydney, NSW 2052, Australia
5School of Medical Sciences, Sydney, NSW 2052, Australia
6SEALS, Anatomical Pathology, St George Hospital, Kogarah, NSW 2217, Australia
7School of Medicine, Deakin University, Waurn Ponds, Victoria 3217, Australia
8Department of Urology, St George Hospital, Kogarah, NSW 2217, Australia
9Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2019, Australia
Yong Li, email: [email protected]
Jingli Hao, email: [email protected]
Keywords: prostate cancer, proteomics, glycolysis, LDHA, radiotherapy
Received: September 02, 2016 Accepted: September 15, 2016 Published: September 30, 2016
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.
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