Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells

Oncotarget
Igor VujicSusana M Ortiz-Urda

Abstract

Oncogenic NRAS mutations are frequent in melanoma and lead to increased downstream signaling and uncontrolled cell proliferation. Since the direct inhibition of NRAS is not possible yet, modulators of NRAS posttranslational modifications have become an area of interest. Specifically, interfering with NRAS posttranslational palmitoylation/depalmitoylation cycle could disturb proper NRAS localization, and therefore decrease cell proliferation and downstream signaling. Here, we investigate the expression and function of NRAS depalmitoylating acyl protein thioesterases 1 and 2 (APT-1, APT-2) in a panel of NRAS mutant melanoma cells. First, we show that all melanoma cell lines examined express APT-1 and APT-2. Next, we show that siRNA mediated APT-1 and APT-2 knock down and that the specific APT-1 and -2 inhibitors ML348 and ML349 have no biologically significant effects in NRAS mutant melanoma cells. Finally, we test the dual APT-1 and APT-2 inhibitor palmostatin B and conclude that palmostatin B has effects on NRAS downstream signaling and cell viability in NRAS mutant melanoma cells, offering an interesting starting point for future studies.

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Citations

Dec 15, 2017·Critical Reviews in Biochemistry and Molecular Biology·Sang Joon WonBrent R Martin
Jul 13, 2018·Critical Reviews in Biochemistry and Molecular Biology·María-Eugenia Zaballa, F Gisou van der Goot
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Aug 7, 2019·Cell Communication and Signaling : CCS·Philipp ZinglerJürgen Fritsch
Jun 8, 2021·Frontiers in Cell and Developmental Biology·Chee Wai Fhu, Azhar Ali
Aug 15, 2021·Neurobiology of Disease·Fanny L LemariéMichael R Hayden

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Methods Mentioned

BETA
GTPases
flow
dot blots
flow cytometry
GTPase
xenograft
Assay
Protein Assay

Software Mentioned

CFlow
CalcuSyn
ImageJ
Gen5

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