Abstract
Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiation factor gene EIF4E3 was among the Nrf2 target genes upregulated in LP-1/Cfz cells, suggesting existence of a positive feedback loop. In line with this, we found that siRNA knockdown of eIF4E3 decreased Nrf2 protein levels. On the other hand, elevated SQSTM1/p62 levels were due at least in part to activation of the PERK-eIF2α pathway. LP-1/Cfz cells had decreased levels of reactive oxygen species as well as elevated levels of fatty acid oxidation and prosurvival autophagy. Genetic and pharmacologic inhibition of the Nrf2-EIF4E3 axis or the PERK-eIF2α pathway, disruption of redox homeostasis or inhibition of fatty acid oxidation or autophagy conferred sensitivity to carfilzomib. Our findings were supported by clinical data where increased EIF4E3 expression was predictive of Nrf2 target gene upregulation in a subgroup of patients with chemoresistant minimal residual disease and relapsed/refractory MM. Thus, our data offer a preclinical rationale for including inhibitors of the SQSTM1/p62-Nrf2 pathway to the treatment regimens for certain advanced stage MM patients.
Highlights
Multiple myeloma (MM) is a B cell malignancy characterized by the clonal expansion of neoplastic plasma cells in the bone marrow
We report the establishment of a new carfilzomib-resistant derivative of the LP-1 MM cell line, LP-1/Cfz, in which carfilzomib resistance was characterized by induction of prosurvival autophagy as well as nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2) pathway activation associated with elevated sequestosome 1 (SQSTM1)/p62 levels
To determine whether Nrf2 translation might be regulated via eIF4E1-eIF4E3 interplay, we investigated the effect of mitogen-activated protein kinase interacting kinases (MNK) inhibition on Nrf2 protein levels in LP-1/Cfz and parental LP-1 cells
Summary
Multiple myeloma (MM) is a B cell malignancy characterized by the clonal expansion of neoplastic plasma cells in the bone marrow. We report the establishment of a new carfilzomib-resistant derivative of the LP-1 MM cell line, LP-1/Cfz, in which carfilzomib resistance was characterized by induction of prosurvival autophagy as well as Nrf pathway activation associated with elevated SQSTM1/p62 levels. Gene set enrichment analysis (GSEA) of gene expression profiling data from MM patient samples showed that increased EIF4E3 expression was predictive of Nrf activation in some chemoresistant minimal residual disease and relapsed/ refractory MM cases These findings have elucidated further complexities of the proteostasis network in MM cells and provide preclinical rationale for therapeutic development of SQSTM1/p62-Nrf inhibitors as a means to overcome proteasome inhibitor resistance in a subgroup of advanced stage MM patients
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