Persistent Link:
http://hdl.handle.net/10150/579327
Title:
Fibronectin Enhances Carfilzomib Mediated Cell Death
Author:
Ramos, Paulina Joanna
Issue Date:
2015
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Cell Adhesion Mediated Drug Resistance (CAM-DR) is a factor in Multiple Myeloma (MM) drug resistance. Despite advances in treatment, multiple myeloma remains incurable and often results in drug resistance. It is known that cell adhesion to fibronectin via integrin β1 confers survival in myeloma cells. We show here that adherence of the NCI-H929 and MM.1S myeloma cells to fibronectin, promotes cell death when treated with proteasome inhibitor Carfilzomib (Kyprolis). These data are in contrast to other cytotoxic drugs, such as melphalan or doxorubicin, and different myeloma cell lines in which the CAM-DR survival phenotype is expressed. We found a significant amount of death in myeloma cells adhered to fibronectin when exposed to carfilzomib. In addition, we demonstrate that pan-caspase inhibitor, Q-VD-OPH, inhibits cell death in myeloma cells in suspension. Carfilzomib cytotoxicity is caspase dependent in suspension. We propose that the increased cytotoxicity in cells adhered to fibronectin may be caspase independent, perhaps due to failed autophagy. These data support the hypothesis that β1 mediated adhesion to fibronectin induces an autophagic response in MM cells contributing to CAM-DR phenotype. We propose that further induction of autophagy by proteasome inhibitors exceeds the adaptive threshold survival response and initiates caspase independent cell death.
Type:
text; Electronic Thesis
Degree Name:
B.S.
Degree Level:
bachelors
Degree Program:
Honors College; Molecular and Cellular Biology
Degree Grantor:
University of Arizona
Advisor:
Landowski, Terry H.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleFibronectin Enhances Carfilzomib Mediated Cell Deathen_US
dc.creatorRamos, Paulina Joannaen
dc.contributor.authorRamos, Paulina Joannaen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.abstractCell Adhesion Mediated Drug Resistance (CAM-DR) is a factor in Multiple Myeloma (MM) drug resistance. Despite advances in treatment, multiple myeloma remains incurable and often results in drug resistance. It is known that cell adhesion to fibronectin via integrin β1 confers survival in myeloma cells. We show here that adherence of the NCI-H929 and MM.1S myeloma cells to fibronectin, promotes cell death when treated with proteasome inhibitor Carfilzomib (Kyprolis). These data are in contrast to other cytotoxic drugs, such as melphalan or doxorubicin, and different myeloma cell lines in which the CAM-DR survival phenotype is expressed. We found a significant amount of death in myeloma cells adhered to fibronectin when exposed to carfilzomib. In addition, we demonstrate that pan-caspase inhibitor, Q-VD-OPH, inhibits cell death in myeloma cells in suspension. Carfilzomib cytotoxicity is caspase dependent in suspension. We propose that the increased cytotoxicity in cells adhered to fibronectin may be caspase independent, perhaps due to failed autophagy. These data support the hypothesis that β1 mediated adhesion to fibronectin induces an autophagic response in MM cells contributing to CAM-DR phenotype. We propose that further induction of autophagy by proteasome inhibitors exceeds the adaptive threshold survival response and initiates caspase independent cell death.en
dc.typetexten
dc.typeElectronic Thesisen
thesis.degree.nameB.S.en
thesis.degree.levelbachelorsen
thesis.degree.disciplineHonors Collegeen
thesis.degree.disciplineMolecular and Cellular Biologyen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorLandowski, Terry H.en
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