AuthorRamos, Paulina Joanna
AdvisorLandowski, Terry H.
MetadataShow full item record
PublisherThe University of Arizona.
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.
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.
Degree ProgramHonors College
Molecular and Cellular Biology