Extracellular
acidosis (low pH) is a
tumor microenvironmental stressor that has a critical function in the malignant progression and metastatic dissemination of
tumors. To survive under stress conditions,
tumor cells must evolve resistance to stress-induced toxicity.
Acyl-CoA synthetase 5 (ACSL5) is a member of the ACS family, which converts
fatty acid to
acyl-CoA. ACSL5 is frequently overexpressed in
malignant glioma, whereas its functional significance is still unknown. Using retrovirus-mediated stable gene transfer (gain of function) and
small interfering RNA-mediated gene silencing (loss of function), we show here that ACSL5 selectively promotes human
glioma cell survival under extracellular
acidosis. ACSL5 enhanced cell survival through its ACS catalytic activity. To clarify the genome-wide changes in cell signaling pathways by ACSL5, we performed
cDNA microarray analysis and identified an ACSL5-dependent gene expression signature. The analysis revealed that ACSL5 was critical to the expression of
tumor-related factors including
midkine (MDK), a
heparin-binding
growth factor frequently overexpressed in
cancer. Knockdown of MDK expression significantly attenuated ACSL5-mediated survival under acidic state. These results indicate that ACSL5 is a critical factor for survival of
glioma cells under acidic tumor microenvironment, thus providing novel molecular basis for
cancer therapy.