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

W. B. Tsai, Y. Long, J. R. Park, J. T. Chang, H. Liu, J. Rodriguez-Canales, Niramol Savaraj, Lynn G Feun, M. A. Davies, I. I. Wistuba, M. T. Kuo

Research output: Contribution to journalArticle

9 Scopus citations

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.Oncogene advance online publication, 22 June 2015; doi:10.1038/onc.2015.237.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jun 22 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Tsai, W. B., Long, Y., Park, J. R., Chang, J. T., Liu, H., Rodriguez-Canales, J., Savaraj, N., Feun, L. G., Davies, M. A., Wistuba, I. I., & Kuo, M. T. (Accepted/In press). Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents. Oncogene. https://doi.org/10.1038/onc.2015.237