Cap dependent translation contributes to resistance of myeloma cells to bortezomib

Translation
Marilena MancinoStefano Biffo

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 bo...Continue Reading

References

Oct 23, 2002·Proceedings of the National Academy of Sciences of the United States of America·Nicholas MitsiadesKenneth C Anderson
Aug 7, 2003·Proceedings of the National Academy of Sciences of the United States of America·Ann-Hwee LeeLaurie H Glimcher
Aug 18, 2004·Genes & Development·Nissim Hay, Nahum Sonenberg
Oct 29, 2004·The New England Journal of Medicine·Robert A Kyle, S Vincent Rajkumar
Jan 22, 2005·Seminars in Cell & Developmental Biology·Christopher G Proud
Dec 17, 2005·Cancer Research·Steffan T NawrockiDavid J McConkey
Feb 20, 2007·Cancer Research·Silke MeisterReinhard E Voll
Jul 25, 2007·Nature Reviews. Cancer·Teru HideshimaKenneth C Anderson
Aug 19, 2007·Cancer Cell·Jonathan J KeatsP Leif Bergsagel
Sep 25, 2007·Experimental Hematology·Mihaela ZleiMonika Engelhardt
Aug 16, 2008·International Review of Cell and Molecular Biology·Oded Meyuhas
Feb 13, 2009·PLoS Biology·Morris E FeldmanKevan M Shokat
Mar 6, 2009·Leukemia Research·Sherif S FaragMichael R Grever
Apr 3, 2009·Nature Reviews. Molecular Cell Biology·Xiaoju Max Ma, John Blenis
Jul 29, 2010·The Journal of Clinical Investigation·Federica Di NicolantonioAlberto Bardelli
Aug 6, 2010·Blood·Bao HoangAlan Lichtenstein
Mar 25, 2011·Nature·Michael A ChapmanTodd R Golub
Nov 3, 2011·Blood·Patricia MaisoIrene M Ghobrial
Jan 19, 2012·Nature Reviews. Molecular Cell Biology·Claudio Hetz
Oct 27, 2012·Cancer Research·Tommy AlainNahum Sonenberg
Dec 18, 2012·Haematologica·Alessandro CampanellaClara Camaschella
Mar 22, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nikhil C Munshi, Kenneth C Anderson

❮ Previous
Next ❯

Methods Mentioned

BETA
density gradient centrifugation
flow cytometry
protein assay
chips
Chip

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.