Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells
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Igor Vujic1,2, Martina Sanlorenzo1,3, Rosaura Esteve-Puig1, Marin Vujic1,2, Andrew Kwong1, Aaron Tsumura1, Ryan Murphy1, Adrian Moy1, Christian Posch2,4, Babak Monshi2, Klemens Rappersberger2, Susana Ortiz-Urda1
1Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA
2Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria
3Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy
4Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Igor Vujic, e-mail: [email protected]
Keywords: NRAS, APT-1, melanoma, palmostatin B, acyl protein thioesterase
Received: August 30, 2015 Accepted: November 22, 2015 Published: January 13, 2016
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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