BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma

Ying Ying Li, Chunjing Wu, Shu Mei Chen, Sumedh S. Shah, Medhi Wangpaichitr, Lynn G Feun, Macus T. Kuo, Miguel Suarez, Jeffrey Prince, Niramol Savaraj

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

BRAF inhibitor (BRAFi) has been used for treatment of melanomas harboring V600E mutation. Despite a high initial response rate, resistance to BRAFi is inevitable. Here, we demonstrate that BRAFi-resistant (BR) melanomas are susceptible to arginine deprivation due to inability to initiate re-expression of argininosuccinate synthetase (ASS1, a key enzyme for arginine synthesis) as well as ineffective autophagy. Autophagy and ASS1 re-expression are known to protect melanoma cells from cell death upon arginine deprivation. When melanoma cells become BR cells by long-term in vitro incubation with BRAFi, c-Myc-mediated ASS1 re-expression and the levels of autophagy-associated proteins (AMPK-α1 and Atg5) are attenuated. Furthermore, our study uncovers that downregulation of deubiquitinase USP28 which results in more active c-Myc degradation via ubiquitin-proteasome machinery is the primary mechanism for inability to re-express ASS1 upon arginine deprivation in BR cells. Overexpression of USP28 in BR cells enhances c-Myc expression and hence increases ASS1 transcription upon arginine deprivation, and consequently leads to cell survival. On the other hand, overexpression of Atg5 or AMPK-α1 in BR cells can redirect arginine deprivation-induced apoptosis toward autophagy. The xenograft models also confirm that BR tumors possess lower expression of ASS1 and are hypersensitive to arginine deprivation. These biochemical changes in BRAFi resistance which make them vulnerable to arginine deprivation can be exploited for the future treatment of BR melanoma patients.

Original languageEnglish (US)
Pages (from-to)17665-17680
Number of pages16
JournalOncotarget
Volume7
Issue number14
DOIs
StatePublished - 2016

Fingerprint

Arginine
Melanoma
Autophagy
AMP-Activated Protein Kinases
Argininosuccinate Synthase
Proteasome Endopeptidase Complex
Ubiquitin
Heterografts
Cell Survival
Cell Death
Down-Regulation
Apoptosis
Mutation
Enzymes
Therapeutics
Neoplasms
Proteins

Keywords

  • Arginine deprivation
  • ASS1 re-expression
  • Autophagy
  • BRAF inhibitor resistance
  • Ubiquitin-proteasome machinery

ASJC Scopus subject areas

  • Oncology

Cite this

BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma. / Li, Ying Ying; Wu, Chunjing; Chen, Shu Mei; Shah, Sumedh S.; Wangpaichitr, Medhi; Feun, Lynn G; Kuo, Macus T.; Suarez, Miguel; Prince, Jeffrey; Savaraj, Niramol.

In: Oncotarget, Vol. 7, No. 14, 2016, p. 17665-17680.

Research output: Contribution to journalArticle

Li, Ying Ying ; Wu, Chunjing ; Chen, Shu Mei ; Shah, Sumedh S. ; Wangpaichitr, Medhi ; Feun, Lynn G ; Kuo, Macus T. ; Suarez, Miguel ; Prince, Jeffrey ; Savaraj, Niramol. / BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma. In: Oncotarget. 2016 ; Vol. 7, No. 14. pp. 17665-17680.
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