title: N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation.
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.
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Dermatology, Massachusetts General Hospital, Charlestown, Massachusetts.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ren@brandeis.edu bjiao@sibs.ac.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiao
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ren@brandeis.edu bjiao@sibs.ac.cn.|Department of Biology, Brandeis University, Waltham, Massachusetts.
authors.forename: Ruibao
authors.initials: R
authors.lastname: Ren
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D051379:Mice; D021381:Protein Transport / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; D016283:Proto-Oncogene Proteins p21(ras); D004298:Dopamine