Published online Mar 21, 2025. doi: 10.3748/wjg.v31.i11.100785
Revised: December 13, 2024
Accepted: February 13, 2025
Published online: March 21, 2025
Processing time: 199 Days and 1.1 Hours
Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells.
To investigate the role of SIRT1 in metabolic reprogramming and overcoming oxaliplatin resistance in CRC cells.
We performed transcriptome sequencing of human CRC parental cells and oxaliplatin-resistant cells to identify differentially expressed genes. Key regulators were identified via the LINCS database. NAD+ levels were measured by flow cytometry, and the effects of SIRT1 on oxaliplatin sensitivity were assessed by MTS assays, colony formation assays, and xenograft models. Glycolytic function was measured using Western blot and Seahorse assays.
Salermide, a SIRT1 inhibitor, was identified as a candidate compound that enhances oxaliplatin resistance. In oxaliplatin-resistant cells, SIRT1 was downregulated, whereas γH2AX and PARP were upregulated. PARP activation led to NAD+ depletion and SIRT1 inhibition, which were reversed by PARP inhibitor treatment. The increase in SIRT1 expression overcame oxaliplatin resistance, and while SIRT1 inhibition increased glycolysis, the increase in SIRT1 inhibited glycolysis in resistant CRC cells, which was characterized by reduced expression of the glycolytic enzymes PKM2 and LDHA, as well as a decreased extracellular acidification rate. The PKM2 inhibitor shikonin inhibited glycolysis and reversed oxaliplatin resistance induced by SIRT1 inhibition.
SIRT1 expression is reduced in oxaliplatin-resistant CRC cells due to PARP activation, which in turn increases glycolysis. Restoring SIRT1 expression reverses oxaliplatin resistance in CRC cells, offering a promising therapeutic strategy to overcome drug resistance.
Core Tip: SIRT1, a NAD+-dependent deacetylase, has demonstrated anti-tumor effects in numerous studies. However, the role of SIRT1 in regulating oxaliplatin resistance remains unclear. This study found that SIRT1 expression is downregulated in oxaliplatin-resistant colorectal cancer (CRC) cell. Enhancing SIRT1 expression reverses this resistance. Mechanistically, DNA damage-induced PARP activation inhibits SIRT1 expression. The inhibition of SIRT1 promotes drug resistance in CRC cells by enhancing glycolysis. These findings highlight the critical role of SIRT1 in oxaliplatin resistance and support the potential of combining SIRT1 agonists with oxaliplatin as a therapeutic strategy to overcome CRC resistance.