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Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

Oncogene volume 35, pages 1632–1642 (2016)Cite this article

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Abstract

Many human malignancies lack de novo biosynthesis of arginine (Arg) as the key enzyme argininosuccinate synthetase 1 (ASS1) is silenced. These tumors acquire ectopic Arg for survival, and depleting this source by Arg-depleting recombinant enzyme ADI-PEG20 results in cell death. Mechanisms underlying Arg auxotrophy in these tumors and how they respond to Arg-auxotrophic stress are poorly understood. Here, we report that an immediate-early event of Arg-auxotrophic response involves reactive oxygen species-mediated secretion of Gas6, which interacts with its receptor Axl and activates the downstream Ras/PI3K/Akt growth signal leading to accumulation of c-Myc by protein stabilization. Arg-auxotrophic challenge also transcriptionally upregulates c-Myc expression, which provides a feedback mechanism to enhance Axl expression. c-Myc is a positive regulator of ASS1, but elevated ASS1 provides a feedback mechanism to suppress c-Myc and Axl. Our results revealed multiple inter-regulatory pathways in Arg-auxotrophic response, consisting of Axl, c-Myc and ASS1, which regulate Arg homeostasis and ADI-PEG20 sensitivity. These pathways provide potential targets for improving the efficacy of treating Arg-auxotrophic tumors using Arg-deprivation strategies.

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Acknowledgements

We thank Drs Bor-Wen Wu and John S Bomalaski (Polaris Pharmacologies) for ADI-PEG20 and anti-ASS1 antibody, Drs RM Melillo, S Jakob and WB Ou for recombinant DNAs. This research was supported in part by the NIH/NCI Grants R01 CA149260 (to MTK) and P30CA16672 (MD Anderson Core).

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Authors and Affiliations

  1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W-B Tsai, Y Long, H Liu, J Rodriguez-Canales, I I Wistuba & M T Kuo

  2. Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Gangwon, Korea

    J-R Park

  3. Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA

    J T Chang

  4. Sylvester Comprehensive Cancer Center, University of Miami, VA Medical Center, Miami, FL, USA

    N Savaraj

  5. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    L G Feun

  6. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M A Davies

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  1. W-B Tsai
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Tsai, WB., Long, Y., Park, JR. et al. Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents. Oncogene 35, 1632–1642 (2016). https://doi.org/10.1038/onc.2015.237

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