title: Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells.
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.
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.|Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Vujic
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.|Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Sanlorenzo
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Rosaura
authors.initials: R
authors.lastname: Esteve-Puig
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.|Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria.
authors.forename: Marin
authors.initials: M
authors.lastname: Vujic
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kwong
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Tsumura
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murphy
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Moy
authors.affiliation: Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria.|Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Posch
authors.affiliation: Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria.
authors.forename: Babak
authors.initials: B
authors.lastname: Monshi
authors.affiliation: Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria.
authors.forename: Klemens
authors.initials: K
authors.lastname: Rappersberger
authors.affiliation: Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Ortiz-Urda
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D011420:Propiolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C578782:palmostatin B; D011420:Propiolactone; C402226:LYPLA1 protein, human; C581317:LYPLA2 protein, human; D013869:Thiolester Hydrolases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: APT-1; NRAS; acyl protein thioesterase; melanoma; palmostatin B