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Oncotarget. 2016 Jan 13. pii: 6907. doi: 10.18632/oncotarget.6907

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

Vujic I¹, Sanlorenzo M², Esteve-Puig R³, Vujic M⁴, Kwong A⁵, Tsumura A⁶, Murphy R⁷, Moy A⁸, Posch C⁹, Monshi B¹⁰, Rappersberger K¹¹, Ortiz-Urda S¹²

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¹University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
²University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
³University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
⁴University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
⁵University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
⁶University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
⁷University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
⁸University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
⁹The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Vienna, Austria.
¹⁰The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Vienna, Austria.
¹¹The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Vienna, Austria.
¹²University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.

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.

KEYWORDS: APT-1, NRAS, acyl protein thioesterase, melanoma, palmostatin B

Publikations ID: 26771141
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