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Cap dependent translation contributes to resistance of myeloma cells to bortezomib. | LitMetric

AI Article Synopsis

  • Multiple myeloma (MM) is a significant blood cancer, and while proteasome inhibitors like bortezomib have improved survival rates, many patients eventually develop resistance to these treatments.
  • The study explores the relationship between protein translation and the toxicity of bortezomib, finding that bortezomib does not induce cell death by increasing pro-apoptotic protein levels but instead reduces the initiation of translation over time.
  • The research suggests that targeting the mTOR pathway could provide an effective treatment option for bortezomib-resistant MM patients, particularly those with differing levels of translation-related proteins eIF4E/4E-BPs.

Article Abstract

Multiple myeloma (MM) is the second most predominant blood malignancy. Proteasome inhibitors like bortezomib have increased life expectancy, but eventually patients develop resistance to therapy. It was proposed that bortezomib acts through the induction of the Unfolded Protein Response (UPR), i.e., accumulation of misfolded proteins causing a lethal stress response. By this theory, increasing the proteasome load by the stimulation of translation may worsen the UPR. Here we evaluated the crosstalk between translation and bortezomib toxicity in both bortezomib sensitive and resistant cells. We found that bortezomib toxicity does not correlate with induction of proapoptotic eIF2α phosphorylation, but rather caused a late reduction in initiation of translation. This effect was accompanied by dephosphorylation of the mTORC1 target 4E-BP1. Infection of myeloma cells with constitutively dephosphorylated 4E-BP1, worsened bortezomib induced cell death. Since mTORC1 inhibitors cause pharmacological inhibition of 4E-BP1 phosphorylation, we tested whether they could act synergistically with bortezomib. We found that both rapamycin, a specific mTORC1 blocker, and PP242 a mTOR antagonist induce the arrest of myeloma cells irrespective of bortezomib sensitivity. Sensitivity to mTOR inhibitors has been associated to the levels of eIF4E/4E-BPs. We found that levels of eIF4E and 4E-BPs are variable among patients, and that 15% of myeloma patients have increased levels of 4E-BP1/2. Primary cells of myeloma retain sensitivity to mTOR inhibition, when plated on stromal cells. We propose that translational load does not contribute to bortezomib-induced death, but rather mTOR targeting may be successful in bortezomib resistant patients, stratified for eIF4E/4EBPs.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718057PMC
http://dx.doi.org/10.4161/trla.27245DOI Listing

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