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.

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…Lactate acts as a powerful regulator of multiple hallmarks of cancer, supporting cell proliferation and promoting immune suppression, angiogenesis, migration, metastasis, and resistance to therapy (20), namely chemotherapy (77), radiotherapy (78), and targeted therapy (79,80). Cancer cells exploiting aerobic glycolysis upregulate GLUTs and MCTs, secreting large amounts of lactate (Figure 1), while deviating glycolytic intermediates to fuel alternative anabolic pathways (e.g., pentose phosphate pathway), thus sustaining rapid cell proliferation (81).…”

Role of metabolism in cancer cell radioresistance and radiosensitization methods

“…Lactate dehydrogenase (LDHA) is found in almost all human tissues; it is a major enzyme catalyzing the conversion of pyruvate to lactic acid, and plays an important role in the glycolytic process [ 105 ]. Michael et al [ 106 – 108 ] demonstrated that LDH5 overexpression can indicate hypoxic conditions, which can be associated with local recurrence, distant metastases, lower overall survival, and radioresistance of head and neck squamous cell carcinoma, prostate, and bladder cancers.…”

“…Furthermore, soluble adenylate cyclase (sAC) promotes the release of LDHA, accelerates cell proliferation, and induces the anti-irradiation effects in prostate cancer cells through the activation of BRAF/ERK1/2 signaling pathway [ 109 ]. FX-11, a specific inhibitor of LDHA, can promote the generation of DSBs and cell apoptosis by reducing the EMT, DNA repair capacity, hypoxia, and autophagy in prostate cancer cells, improving cell sensitivity to radiotherapy [ 105 ]. Acting as a tumor suppressor, the expression of miR-34 was shown to negatively correlate with radioresistance development and to induce the sensitivity of the hepatocellular carcinoma cells to radiotherapy by inhibiting the expression of LDHA (Fig.…”

Targeting cancer-cell mitochondria and metabolism to improve radiotherapy response

“… [98] Hao, J. et al. Prostate Increased LDHA [99] Glutamine metabolism Li, D. et al. Pancreatic Non-canonical glutamine metabolism pathway [107] Xiang, L. et al.…”