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Mechanisms of a Function‐Selective ERK Inhibitor and Induction of Apoptosis in Melanoma Cells
Author(s) -
Martinez Ramon,
Huang Weiliang,
Mackowiak Bryan,
Shapiro Paul
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.815.6
Subject(s) - mapk/erk pathway , programmed cell death , apoptosis , oxidative stress , microbiology and biotechnology , cell growth , melanoma , reactive oxygen species , allosteric regulation , chemistry , protein kinase a , downregulation and upregulation , kinase , cancer research , biology , biochemistry , enzyme , gene
Various cancer cell types can contribute their proliferative phenotypes to mutations conferring constitutive activity of the extracellular signal‐regulated kinase (ERK1/2) signaling pathway. Recent trends in drug design have suggested that shifting the design of ERK1/2 pathway inhibitors from targeting the catalytic core of the kinase to allosteric inhibition may prove as a promising alternative to therapeutic development. We previously identified a novel thienyl naphthalene sulfonate compound that shows functionally‐selective inhibitory activity against ERK2 by blocking F‐site containing substrates, including Fos family proteins. Proteomic analysis of drug‐treated melanoma cell lysates suggests that treatment with this novel compound results in defects in mitochondrial function as well as upregulation of markers suggestive of activating an oxidative stress response. As well, further mass spectrometry analysis has suggested that the novel compound may generate covalent modifications on cysteine residues of the ERK2 protein. Additional studies with inhibitors of various reactive oxygen species (ROS) have shown that while the generation of ROS may be evident with compound treatment, further cell viability study has indicated that ROS is only partially responsible for the growth inhibition of melanoma cells. In these studies, we provide further insight into the interactions this novel compound makes with the ERK2 protein, and the transcriptomic and proteomic responses that ultimately result in oxidative stress and melanoma cell death. Support or Funding Information This work was supported by an NIGMS Institutional Training Grant (T32 GM066706). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .