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, N. Savaraj, L. G. Feun, M. A. Davies, I. I. Wistuba, M. T. Kuo

Research output: Contribution to journalArticlepeer-review

12 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 speciesmediated 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.

Original languageEnglish (US)
Pages (from-to)1632-1642
Number of pages11
JournalOncogene
Volume35
Issue number13
DOIs
StatePublished - Mar 31 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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