1,25(OH)2D3 disrupts glucose metabolism in prostate cancer cells leading to a truncation of the TCA cycle and inhibition of TXNIP expression

Abstract

Prostate cell metabolism exhibits distinct profiles pre- and post-malignancy. The malignant metabolic shift converts prostate cells from "citrate-producing" to "citrate-oxidizing" cells, thereby enhancing glucose metabolism, a phenotype that contrasts classical tumoral Warburg metabolism. An on-line biosensor chip system (BIONAS 2500) was used to monitor metabolic changes (glycolysis and respiration) in response to the putative anti-cancer nutraceutical 1,25-dihydroxyvitamin D [1,25(OH)D], in different prostate cancer (PCa) cell lines (LNCaP, VCaP, DU145 and PC3). LNCaP cells exhibited profound metabolic responsiveness to the treatment and thus extensive analysis of metabolism-modulating effects of 1,25(OH)D were performed, including mRNA expression analysis of key metabolic genes (e.g. GLUT1 and PDHK1), analysis of TCA cycle metabolites, glucose uptake/consumption measurements, ATP production, and mitochondrial biogenesis/activity. Altogether, data demonstrate a vivid disruption of glucose metabolism by 1,25(OH)D, illustrated by a decreased glucose uptake and an accumulation of citrate/isocitrate due to TCA cycle truncation. Depletion of glycolytic intermediates led to a consistent decrease in TXNIP expression in response to 1,25(OH)D, an effect that coincided with the activation of AMPK signaling and a reduction in c-MYC expression. Reduction in TXNIP levels in response to 1,25(OH)D was rescued by an AMPK signaling inhibitor and mimicked by a MYC inhibitor highlighting the possible involvement of both pathways in mediating 1,25(OH)D's metabolic effects in PCa cells. Furthermore, pharmacological and genetic modulation of the androgen receptor showed similar and disparate effects on metabolic parameters compared to 1,25(OH)D treatment, highlighting the AR-independent nature of 1,25(OH)D's metabolism-modulating effects.

Combined antitumor effects of 1,25‑dihydroxy vitamin�D3 and Notch inhibitor in liver cancer

“…1,25(OH) 2 D 3 functions mainly through binding to a specific vitamin D receptor to inhibit myeloid leukemia cell proliferation (33). Previous studies have shown that 1,25(OH) 2 D 3 can inhibit tumor cell proliferation, reduce tumor cell migration and invasion, and induce apoptosis of prostate cancer cells (34). The results of the present study confirmed that 1,25(OH) 2 D 3 exerted anticancer activity in liver cancer cells.…”

Long Non-coding RNA MEG3 Activated by Vitamin D Suppresses Glycolysis in Colorectal Cancer via Promoting c-Myc Degradation

“…Lactate production also increased consistently after VDR knockdown in MEG3-overexpressed cells (Figure 6B). Previous studies have shown that vitamin D decreases glycolysis in various cancers, including CRC (23)(24)(25). We speculated whether MEG3 mediated vitamin D-induced inhibition of glycolysis.…”

Glucose-6-Phosphate Upregulates Txnip Expression by Interacting With MondoA

“…MondoA undertakes a vital role in metabolism and multiple target genes are dedicated to its activity. The MondoA/Mlx-Txnip metabolic regulation pathway are implicated an substantial role in the occurrence and development of many diseases, such as the first and second most common causes of premature mortality, cancer (Abu el Maaty et al, 2017, 2019 and diabetes (Szpigel et al, 2018). Therefore, research on this pathway is an important aspect of identifying the cause and finding curable strategy.…”