# ACSL5 Regulates Glucose Metabolism and Chemotherapy Sensitivity in Colorectal Cancer Cells under Glutamine Deficiency

## TL;DR

ACSL5 helps cancer cells survive without glutamine by boosting metabolism, but this makes them more sensitive to chemotherapy.

## Contribution

ACSL5's role in metabolic reprogramming and chemotherapy sensitivity under glutamine deficiency is newly identified.

## Key findings

- ACSL5 upregulation sustains tumor cell viability through enhanced glycolysis and oxidative phosphorylation.
- ACSL5 increases ROS and weakens DNA repair, making cells more responsive to oxaliplatin chemotherapy.
- ACSL5 operates in a p53 regulatory loop, stabilizing MDM2 and suppressing p53 expression.

## Abstract

Glutamine metabolism is crucial for sustaining tumor cell viability and growth, broadly promoting prospects for the therapeutic targeting of glutamine dependence. However, further research is needed to address key translational issues, particularly to better understand the adaptive survival responses employed by cancer cells in overcoming nutrient deficiency. Long‐chain acyl‐CoA synthetase 5 (ACSL5) is found to be upregulated under glutamine deprivation, acting to sustain tumor cell viability by enhancing both glycolytic flux and oxidative phosphorylation. ACSL5 operates within a p53 regulatory loop: p53 transcriptionally upregulates ACSL5, while ACSL5 competes with MIB1 to stabilize MDM2, suppressing p53 expression. Mechanistically, ACSL5 relieves p53‐mediated inhibition of PGAM1 to drive glycolysis, while its mitochondrial localization promotes IDH2 activation to accelerate the TCA cycle. Nonetheless, these metabolic increases also generate reactive oxygen species (ROS), inducing DNA damage and significantly enhancing colorectal cancer cell sensitivity to oxaliplatin. The latter provides an explanation as to why colorectal tumors with high ACSL5 expression display preferentially improved patient outcomes from chemotherapy. Collectively, the findings reveal a new pathway for non‐genetic chemotherapy resistance mechanisms, deepen the understanding of metabolic reprogramming in tumor cells, and offer potential therapeutic targets for future treatment strategies.

Glutamine deprivation triggers ACSL5 upregulation in tumor cells, sustaining their viability via dual metabolic rewiring programs. ACSL5 enhances glycolysis by relieving p53's inhibition of PGAM1 while also sustaining mitochondrial respiration and TCA cycle flux through promoting IDH2 dimerization. This comes at a cost, elevated ROS and weakened p53 dependent DNA repair mechanisms sensitize tumor cells to oxaliplatin chemotherapy.