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

Oncogene volume 28, pages 9–19 (2009)Cite this article

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. 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.

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Acknowledgements

We thank the National Cancer Institute as well as T Yamori for providing us SF268 and SNB78 cell lines and S Aaronson and K Mishima for A1207 cell lines. We thank A Tomida, S Saito and A Furuno for technical advice on GeneChip analysis, S Okabe for technical support, and T Migita and members in our laboratory for helpful discussions. This study was supported by a Grant-in-Aid for Cancer Research on Priority Areas and a Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    T Mashima & H Seimiya

  2. Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    S Sato

  3. Department of Chemotherapy, Faculty of Pharmacy, KEIO University, Tokyo, Japan

    Y Sugimoto

  4. Division of Gene Therapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Y Sugimoto

  5. Director's Room, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    T Tsuruo

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  1. T Mashima
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Correspondence to H Seimiya.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Mashima, T., Sato, S., Sugimoto, Y. et al. Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions. Oncogene 28, 9–19 (2009). https://doi.org/10.1038/onc.2008.355

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