Nrf2: not “lost in translation”

Increased expression of the tight junction protein TJP1/ZO-1 is associated with upregulation of TAZ-TEAD activity and an adult tissue stem cell signature in carfilzomib-resistant multiple myeloma cells and high-risk multiple myeloma patients

“…Strikingly, TEAD1 protein levels were also markedly increased in LP-1/Cfz cells (Figure 3B ). These findings were reminiscent of the translational upregulation we previously documented for Nrf2 in LP-1/Cfz cells [ 8 , 9 ]. Importantly, combined knockdown of TAZ and TEAD1 with previously validated siRNAs [ 37 , 38 ] partially sensitized LP-1/Cfz cells to carfilzomib (P = 0.04; Figure 3C-E ).…”

“…Consistent with the post-transcriptional increase in TEAD1 (and, to some degree, TAZ) levels and the translational adaptations that resulted in increased Nrf2 protein levels in LP-1/Cfz cells [ 8 , 9 ], pathways related to translational control of gene expression were among the overrepresented processes shared with TJP1-up patients (Figures 5D , 6B ; Table S1 : C2.CP Canonical pathways, C5 GO gene sets). In a complementary approach, when we queried the Connectivity Map database (CMap Build 02), a reference collection of 6,100 gene expression signatures from four human cell lines treated with 1,309 small molecule perturbagens [ 22 ], we identified gene expression perturbations by cycloheximide and emetine as the only ones that were significantly negatively correlated with the expression signatures linked to both carfilzomib resistance in LP-1/Cfz cells and the TJP1-up MM cases (P ≤ 0.05) ( Table S1 : CMap Build 02).…”

“…Unfortunately, however, MM patients routinely develop resistance to proteasome inhibitor-based therapies and eventually succumb to their disease [ 2 - 5 ]. Toward identification of novel agents that will overcome resistance to this class of anti-MM drugs, we have developed isogenic models of carfilzomib resistance using a panel of patient-derived MM cell lines [ 6 - 9 ]. Our studies have revealed upregulated expression of the ABCB1/P-glycoprotein multidrug resistance efflux transporter, elevated prosurvival autophagy and antioxidant defense, altered intermediary metabolism and reprogramming of the translation machinery as key processes mediating acquired resistance to carfilzomib [ 6 - 9 ].…”

“…We confirmed the CMap prediction by showing that homoharringtonine (omacetaxine mepesuccinate) — the first translation inhibitor to be approved by the U.S. Food and Drug Administration — displayed potent cytotoxic activity on LP-1/Cfz cells. Cytotoxicity was associated with decreased TAZ and TEAD1 protein levels as well as two proteins, Nrf2 and MCL1, previously identified by us and others as contributing to MM drug resistance [ 8 , 9 , 23 - 25 ].…”

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

“…Whereas SULF1 was previously shown to be induced by TNFα in MRC-5 fibroblasts [33], we found no clear activators for OXTR, but indications that proinflammatory cytokines such as IL-1β, IL-6, and TNFα might induce its transcription [34]. For the activation of NQO1 and the correlating genes FTH1, FTL, and SQSTM1, several reports pointed to the transcription factor NFE2L2 (also known as NRF2) [35][36][37].…”