Study of proteasome regulation in Multiple Myeloma patients treated with therapeutic proteasome inhibitors

Postgraduate Thesis uoadl:2820750 314 Read counter

Unit:
Κατεύθυνση Εφαρμογές της Βιολογίας στην Ιατρική
Library of the School of Science
Deposit date:
2018-11-29
Year:
2018
Author:
Minagia Maria
Supervisors info:
Ιωάννης Π. Τρουγκάκος
Αναπληρωτής Kαθηγητής, Τομέας Βιολογίας Κυττάρου και Βιοφυσικής,
Τμήμα Βιολογίας, ΕΚΠΑ.
Original Title:
Μελέτη της πρωτεασωμικής λειτουργίας σε ασθενείς πολλαπλού μυελώματος μετά τη χορήγηση θεραπευτικών πρωτεασωμικών αναστολέων
Languages:
Greek
Translated title:
Study of proteasome regulation in Multiple Myeloma patients treated with therapeutic proteasome inhibitors
Summary:
Abstract
Multiple Myeloma (MM) is a hematological malignancy caused by the transformation of B-lymphocytes into pathological clonal plasma cells that accumulate in the bone marrow and secrete high amounts of monoclonal immunoglobulin (IgG). A promising therapeutic approach is to target the proteasome, using various proteasome inhibitors (PIs). PIs are short peptides that bind to the catalytic sites of proteasome subunits and thus prevent proper proteasome function. Proteasome dysfunction leads to the accumulation of unfolded proteins and results in disproportionate apoptosis of myeloma cells.
Herein, we studied proteasome regulation in peripheral blood mononuclear cells (PBMCs; represent cell lineages with active genomic responses), and red blood cells (RBCs; represent an anucleate relatively “long-lived” proteome) isolated from MM patients treated with Carfilzomib.
Our findings showed that proteasome activity in both PBMCs and RBCs was immediately suppressed after PI treatment in all patients, resulted in gene expression increase of ubiquitin-proteasome system components, in order to overcome the inhibitory effect of PIs. In addition, it was found that PIs led in induction of the expression levels of antioxidant enzymes, chaperones and aggresomes removal/autophagy components. The activation of additional PN modules upon proteasome inhibition is supported by our finding of minimal correlation between the levels of proteome ubiquitination/carbonylation in PBMCs and the level of proteasome activity downregulation.
Considering the above, we conclude that the measurement of proteasome activities after administration of PIs is a matter of necessity in order to adjust the dosage protocol for a more personalized therapeutic approach. In addition, we propose that a correlation between the transcriptional regulation of autophagy, antioxidant enzymes, molecular chaperones and patients’ clinical outcomes, such as overall survival and progression-free survival, could reveal possible prognostic markers in order to evaluate and develop combination therapy for MM patients.
Main subject category:
Health Sciences
Keywords:
proteasome inhibitors, proteasome, autophagy, oxidative stress, Multiple Myeloma, ubiquitin-proteasome system, protein degradation, autophagy-lysosome system, apoptosis, unfold protein response.
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
141
Number of pages:
105
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