title: Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents.
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.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: W-B
authors.initials: WB
authors.lastname: Tsai
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Gangwon, Korea.
authors.forename: J-R
authors.initials: JR
authors.lastname: Park
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, VA Medical Center, Miami, FL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Savaraj
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Feun
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: I I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Kuo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001120:Arginine / Q000096:biosynthesis* / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000970:Antineoplastic Agents; D001120:Arginine; D006867:Hydrolases; D036341:Intercellular Signaling Peptides and Proteins; D011092:Polyethylene Glycols; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C512527:ADI PEG20; C000722289:AXL protein, human