N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation.

Min Wu,Jianming Zhang,Cyril Benes,Ruibao Ren,Bo Jiao,Jinyan Huang

doi:10.1158/1535-7163.mct-16-0419

Abstract

RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block RAS oncogenic signaling by a distinct mechanism. Because the biological activity of RAS proteins relies upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS-specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors. Further analyses show that NADA is more active in inhibiting the NRAS transformation and signaling than that of KRAS4B. Mechanistically, NADA blocks the plasma membrane translocation of NRAS, but not that of KRAS4B. In addition, NADA inhibits plasma membrane translocation and neoplastic transformation of oncogenic KRAS4A. Interestingly, NADA also redistributes the cytoplasmic NRAS to the Golgi apparatus in a palmitoylation-dependent manner. The results indicate that NADA inhibits NRAS and KRAS4A plasma membrane translocation by targeting a novel molecular process. The new findings would help to develop novel targeted therapies for a broad range of human cancers. Mol Cancer Ther; 16(1); 57-67. ©2016 AACR.

Highlights

RAS proteins are small GTPases that act as molecular switches, transducing signals from many activated receptors that regulate cell proliferation, survival, and differentiation [1]
We found that N-arachidonoyl dopamine (NADA) inhibits the NRAS oncogenic transformation by suppressing its plasma membrane translocation
Oncogenic mutations of NRAS account for 12% of RAS mutations in human cancer [45]

Summary

Introduction

RAS proteins are small GTPases that act as molecular switches, transducing signals from many activated receptors that regulate cell proliferation, survival, and differentiation [1]. The mammalian RAS include four highly homologous proteins: H-, N-, KRAS4A, and 4B, the latter two being alternatively spliced forms [2]. Because the enzymatic activity of RAS is used to turn itself off and its GTP binding affinity is very high, RAS proteins have been difficult to target [4]. Despite intensive research over three decades, cancers harboring RAS mutations remain the most difficult to treat and are refractory to current targeted therapies [5]. Identification of alternative targets that block RAS signaling is critical to develop therapies for RAS mutation-driven cancer

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Results

Conclusion