title: Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells.
abstract: Melanomas and other cancers that do not express argininosuccinate synthetase (AS), the rate-limiting enzyme for arginine biosynthesis, are sensitive to arginine depletion with pegylated arginine deiminase (ADI-PEG20). However, ADI resistance eventually develops in tumors because of AS upregulation. Although it has been shown that AS upregulation involves c-Myc, the underlying mechanisms remain unknown. Here we show that ADI-PEG20 activates Ras signaling and the effector extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT/GSK-3β kinase cascades, resulting in phosphorylation and stabilization of c-Myc by attenuation of its ubiquitin-mediated protein degradation mechanism. Inhibition of the induced cell signaling pathways using PI3K/AKT inhibitors suppressed c-Myc induction and enhanced ADI-mediated cell killing. Notably, in an animal model of AS-negative melanoma, combination therapy using a PI3K inhibitor plus ADI-PEG20 yielded additive antitumor effects as compared with either agent alone. Taken together, our findings offer mechanistic insight into arginine deprivation metabolism and ADI resistance, and they illustrate how combining inhibitors of the Ras/ERK and PI3K/AKT signaling pathways may improve ADI-PEG20 anticancer responses.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77053, USA.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Tsai
authors.forename: Isamu
authors.initials: I
authors.lastname: Aiba
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.forename: Lynn
authors.initials: L
authors.lastname: Feun
authors.forename: Niramol
authors.initials: N
authors.lastname: Savaraj
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001124:Argininosuccinate Synthase / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D011905:Genes, ras; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D058539:Phosphatidylinositol 3-Kinase; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction; D025801:Ubiquitin; D015854:Up-Regulation
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D025801:Ubiquitin; D011092:Polyethylene Glycols; D058539:Phosphatidylinositol 3-Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D006867:Hydrolases; C512527:ADI PEG20; C019723:arginine deiminase; D001124:Argininosuccinate Synthase