The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.

Synthetic oleanane triterpenoids (SOTs) are small molecules with broad anticancer properties. A recently developed SOT, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole (CDDO-2P-Im or '2P-Im'), exhibits enhanced activity and improved pharmacokinetics over CDDO-Im, a previous generation SOT. However, the mechanisms leading to these properties are not defined. Here, we show the synergy of 2P-Im and the proteasome inhibitor ixazomib in human multiple myeloma (MM) cells and 2P-Im activity in a murine model of plasmacytoma. RNA sequencing and quantitative reverse transcription PCR revealed the upregulation of the unfolded protein response (UPR) in MM cells upon 2P-lm treatment, implicating the activation of the UPR as a key step in 2P-Im-induced apoptosis. Supporting this hypothesis, the deletion of genes encoding either protein kinase R-like endoplasmic reticulum kinase (PERK) or DNA damage-inducible transcript 3 protein (DDIT3; also known as CHOP) impaired the MM response to 2P-Im, as did treatment with ISRIB, integrated stress response inhibitor, which inhibits UPR signaling downstream of PERK. Finally, both drug affinity responsive target stability and thermal shift assays demonstrated direct binding of 2P-Im to endoplasmic reticulum chaperone BiP (GRP78/BiP), a stress-inducible key signaling molecule of the UPR. These data reveal GRP78/BiP as a novel target of SOTs, and specifically of 2P-Im, and suggest the potential broader utility of this class of small molecules as modulators of the UPR.

'Bending' models of halotropism: incorporating protein phosphatase 2A, ABCB transporters, and auxin metabolism.

Salt stress causes worldwide reductions in agricultural yields, a problem that is exacerbated by the depletion of global freshwater reserves and the use of contaminated or recycled water (i.e. effluent water). Additionally, salt stress can occur as cultivated areas are subjected to frequent rounds of irrigation followed by periods of moderate to severe evapotranspiration, which can result in the heterogeneous aggregation of salts in agricultural soils. Our understanding of the later stages of salt stress and the mechanisms by which salt is transported out of cells and roots has greatly improved over the last decade. The precise mechanisms by which plant roots perceive salt stress and translate this perception into adaptive, directional growth away from increased salt concentrations (i.e. halotropism), however, are not well understood. Here, we provide a review of the current knowledge surrounding the early responses to salt stress and the initiation of halotropism, including lipid signaling, protein phosphorylation cascades, and changes in auxin metabolism and/or transport. Current models of halotropism have focused on the role of PIN2- and PIN1-mediated auxin efflux in initiating and controlling halotropism. Recent studies, however, suggest that additional factors such as ABCB transporters, protein phosphatase 2A activity, and auxin metabolism should be included in the model of halotropic growth.