FASEB J. 2022 May;36 Suppl 1
The Warburg effect explains that the cancer cell's metabolism is programmed based on anaerobic glycolysis to support the proliferation and anabolic growth of cancer cells. LDH-A is the form of LDH found in cancer cells, which is the main regulator of anaerobic glycolysis. Increased LDH-A activity; promotes tumor growth and metastasis, increases migration and invasion. The active form of vitamin D (1,25(OH)2 D3 ), can have a protective effect against cancer by acting on apoptosis induction, stimulation of cell differentiation, anti-inflammatory, anti-proliferative effect, angiogenesis, and invasion through different mechanisms. We hypothesis that reprogramming cancer cell's glucose metabolism to oxidative phosphorylation with LDH-A inhibitor will increase the effectiveness of 1,25(OH)2 D3 vitamin in prostate cancer (PCa). For this purpose, 50 male C57BL/6 mice and Tramp-C2 PCa cell lines were used to develop PCa model (1- Control group; 2- PCa control group; 3- 1,25(OH)2 D3 vitamin group (5 µg/kg 1,25(OH)2 D3 vitamin); 4- LDH-A inhibitor (300 mg/kg sodium oxamate) group; 5- Combined group (LDH-A inhibitor + 1,25(OH)2 D3 ). CK18-M30, lactate and oxidative stress values were calculated from serum samples. TUNEL staining for apoptosis analysis, western blot analysis for epithelial to mesenchymal transition (EMT) to evaluate metastasis were performed from tumor tissue samples. Hematoxylin-eosin staining (HE) was performed in the liver and periodic acid schiff staining (PAS) was performed in the kidney tissues to evaluate toxicity. When the serum lactate levels were examined, it was shown that the LDH-A inhibitor reversed the Warburg effect. 1,25(OH)2 D3 , LDH-A inhibitor, and LDH-A inhibitor + 1,25(OH)2 D3 treatment groups significantly increased oxidative stress and apoptosis (p<0.05). Moreover, 1,25(OH)2 D3 treatment group had more toxic effect on the kidney. However, when the two treatments groups were combined, the toxicity of vitamin D was significantly decreased (p<0.05). In the liver, the combined treatment group had more toxic effects than other experimental groups (p>0.05). When the effect on EMT was examined, it was observed that the 1,25(OH)2 D3 , LDH-A inhibitor increased the expression of E-cadherin and decreased the expression of N-cadherin (p<0.05). There was no significant difference between EMT transcription factors in terms of treatment groups (p>0.05). Our results suggest that LDH-A inhibitor + 1,25(OH)2 D3 combined treatment group increased apoptosis, oxidative stress, and decreased toxic effect of 1,25(OH)2 D3 in the kidney. So, tumor volume was decreased and the effectiveness of 1,25(OH)2 D3 vitamin was increased. For metastasis, E-cadherin was increased, and N-cadherin was decreased in the LDH-A inhibitor and 1,25(OH)2 D3 vitamin group. However, the transcription factors results were contradictory. For this reason, EMT results needed to be further research to understand the mechanism. Taken together, our current data indicate that LDH-A inhibitor reprogrammed glucose metabolism and increased effectiveness of 1,25(OH)2 D3 vitamin in PCa animal model.
Keywords: 1,25(OH)2D3; LDH-A Inhibitor; Warburg Effect