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

// Igor Vujic 1, 2 , Martina Sanlorenzo 1, 3 , Rosaura Esteve-Puig 1 , Marin Vujic 1, 2 , Andrew Kwong 1 , Aaron Tsumura 1 , Ryan Murphy 1 , Adrian Moy 1 , Christian Posch 2, 4 , Babak Monshi 2 , Klemens Rappersberger 2 , Susana Ortiz-Urda 1 1 Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA 2 Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria 3 Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy 4 Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Correspondence to: Igor Vujic, e-mail: igor.vujic.md@gmail.com Keywords: NRAS, APT-1, melanoma, palmostatin B, acyl protein thioesterase Received: August 30, 2015      Accepted: November 22, 2015      Published: January 13, 2016 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.