Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells

Wen Bin Tsai, Isamu Aiba, Yan Long, Hui Kuan Lin, Lynn G Feun, Niramol Savaraj, Macus Tien Kuo

Research output: Contribution to journalArticle

84 Citations (Scopus)

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 ADIPEG20 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 ADIPEG20 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.

Original languageEnglish
Pages (from-to)2622-2633
Number of pages12
JournalCancer Research
Volume72
Issue number10
DOIs
StatePublished - May 15 2012

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Argininosuccinate Synthase
1-Phosphatidylinositol 4-Kinase
Extracellular Signal-Regulated MAP Kinases
Melanoma
Mitogen-Activated Protein Kinase 6
Up-Regulation
Arginine
Glycogen Synthase Kinase 3
Ubiquitin
Proteolysis
Neoplasms
Phosphotransferases
Animal Models
Phosphorylation
arginine deiminase
Enzymes
ADI PEG20

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells. / Tsai, Wen Bin; Aiba, Isamu; Long, Yan; Lin, Hui Kuan; Feun, Lynn G; Savaraj, Niramol; Kuo, Macus Tien.

In: Cancer Research, Vol. 72, No. 10, 15.05.2012, p. 2622-2633.

Research output: Contribution to journalArticle

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