BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma

Oncotarget
Ying-Ying LiNiramol Savaraj

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-i...Continue Reading

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Citations

Jan 5, 2017·Molecular Carcinogenesis·Mahamat BabaganaEugene S Kandel
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Methods Mentioned

BETA
FACS
fluorescence microscopy
immunoprecipitation
ubiquitination
xenograft
light microscopy
deubiquitination
PCR
transfection
flow cytometry

Software Mentioned

Image J
Prism
Excel

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