Inhibition of thioredoxin-1 enhances the toxicity of glycolysis inhibitor 2-deoxyglucose by downregulating SLC1A5 expression in colorectal cancer cells

Background: Targeting glycolysis in cancer is an attractive approach for therapeutic intervention. 2-Deoxyglucose (2DG) is a synthetic glucose analog that inhibits glycolysis. However, its efficacy is limited by the systemic toxicity at high doses. Understanding the mechanism of 2DG resistance is important for further use of this drug in cancer treatment.

Methods: The expression of thioredoxin-1 (Trx-1) in colorectal cancer (CRC) cells treated with 2DG was detected by Western blotting. The effect of Trx-1 on the cytotoxicity of 2DG in CRC cells was examined in vitro and in vivo. The molecular mechanism involved in Trx-1-mediated activation of the SLC1A5 gene promoter activity was elucidated using in vitro models.

Results: Inhibition glycolysis with 2DG increased the expression of Trx-1 in CRC cells. Overexpression of Trx-1 decreased the cytotoxicity of 2DG, whereas knockdown of Trx-1 by shRNA significantly increased the cytotoxicity of 2DG in CRC cells. The Trx-1 inhibitor PX-12 increased the cytotoxicity of 2DG on CRC cells both in vitro and in vivo. In addition, Trx-1 promoted SLC1A5 expression by increasing the promoter activity of the SLC1A5 gene by binding to SP1. We also found that the SLC1A5 expression was upregulated in CRC tissues, and inhibition of SLC1A5 significantly enhanced the inhibitory effect of 2DG on the growth of CRC cells in vitro and in vivo. Overexpression of SLC1A5 reduced the cytotoxicity of 2DG in combination with PX-12 treatment in CRC cells.

Conclusion: Our results demonstrate a novel adaptive mechanism of glycolytic inhibition in which Trx-1 increases GSH levels by regulating SLC1A5 to rescue cytotoxicity induced by 2DG in CRC cells. Inhibition of glycolysis in combination with inhibition of Trx-1 or SLC1A5 may be a promising strategy for the treatment of CRC.

 

Comments:

This study seems to provide valuable insights into the resistance mechanisms involving 2-deoxyglucose (2DG) in colorectal cancer (CRC) cells. The findings highlight the role of thioredoxin-1 (Trx-1) in mitigating the cytotoxic effects of 2DG and shed light on its interplay with SLC1A5, a gene involved in the resistance mechanism.

The key takeaways from this research are:

1. **Trx-1 Overexpression and 2DG Resistance:** The study shows that increased Trx-1 expression correlates with reduced cytotoxicity of 2DG in CRC cells. Conversely, knocking down Trx-1 enhances the effectiveness of 2DG, indicating Trx-1's role in mediating resistance to 2DG.

2. **Trx-1 Inhibition Potentiates 2DG Efficacy:** The use of the Trx-1 inhibitor PX-12 amplifies the cytotoxicity of 2DG, both in vitro and in vivo, suggesting that targeting Trx-1 could be a promising approach to overcome 2DG resistance in CRC treatment.

3. **SLC1A5 Regulation by Trx-1:** Trx-1 seems to regulate the expression of SLC1A5, likely by increasing the gene's promoter activity through SP1 binding. SLC1A5, known for its involvement in amino acid transport, appears to contribute to 2DG resistance in CRC cells.

4. **SLC1A5 Inhibition and Enhanced 2DG Sensitivity:** Inhibition of SLC1A5 significantly enhances the inhibitory effect of 2DG on CRC cell growth, suggesting that targeting SLC1A5 could potentiate the impact of 2DG in CRC treatment.

5. **Therapeutic Implications:** Combining glycolysis inhibition with concurrent inhibition of Trx-1 or SLC1A5 emerges as a potentially effective strategy for CRC treatment. This combination could overcome the resistance mechanisms and improve the efficacy of 2DG against CRC cells.

The findings underscore the complexity of cancer cell adaptation to metabolic stress and offer potential therapeutic avenues by identifying specific targets (Trx-1 and SLC1A5) that, when inhibited, could enhance the effectiveness of glycolysis inhibitors like 2DG in CRC treatment.

Related Products

Cat.No.	Product Name	Information
S7947	PX-12	PX-12 (DB05448, 1-methyl propyl 2-imidazolyl disulfide) is a potent thioredoxin-1 (Trx-1) inhibitor by irreversibly thioalkylation of Cys73 of Trx-1. Phase 2.

Related Targets

COVID-19 Thioredoxin