Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

Abstract

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. AcylCoA 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 retrovirusmediated 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.

Multiplex mapping of chromatin accessibility and DNA methylation within targeted single molecules identifies epigenetic heterogeneity in neural stem cells and glioblastoma

“…However, additional studies are required to determine the functional significance of DNA methylation, if any, at these genes. Our finding of differentially methylated/accessible genes previously shown to harbor mutations in GBM-COL19A1 (Sumiyoshi et al 1997), CD93 (Dieterich et al 2012), AGAP2 (Knobbe et al 2005), and ACSL5 (Mashima et al 2009)-supports the validity of this approach in identifying GBM-relevant epigenetic perturbations. Interestingly, most of the genes that were identified as differentially methylated between GBM and NSC were classified as variably methylated in NSC (Table 4, lower).…”

Gene expression profiling predicts response to temozolomide in malignant gliomas

“…Further four genes [namely, midkine (MDK), caspase 1 (CASP1), vitamin D receptor (VDR), and protein-L-isoaspartate O-methyltransferase (PCMT1)], for which the results were significantly correlated in our analyses (with MDK, CASP1 and VDR being positively correlated to TMZ resistance, and PCMT1 negatively correlated to TMZ resistance) (Fig. 2), have previously been reported to be associated with chemotherapy resistance, prognosis, tumor progression, or antiproliferation, in malignant gliomas (25)(26)(27)(28)(29).…”

“…However, again, none of these genes were identified in our microarray analysis. On the other hand, highly significant statistically positive-and negative-correlation of genes concerned with TMZ sensitivity/resistance were found as shown in Tables II and III (25)(26)(27)(28)(29), were differentially expressed in association with TMZ sensitivity/resistance in the glioma-derived cell lines. Among the genes positively correlated to TMZ resistance in our analysis, one of the most noteworthy is MGMT, as mentioned above; MGMT expression provides a resistance measure that can potentially be applied to current TMZ-based treatment strategies for malignant glioma patients.…”

De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy

“…ACSL5, another ACS isoform, plays a role in the pathogenesis of cancer. It is frequently overexpressed in malignant gliomas and is involved in their growth and survival (Yamashita et al, 2000;Mashima et al, 2009). Studies with a specific inhibitor of ACS, Triacsin c, further revealed that ACS inhibition induces selective apoptosis in cancer cells through the mitochondria-mediated pathway (Mashima et al, 2005).…”