School of Medicine and Health Sciences Poster Presentations
NRF2-P62 Contribute to Resistance to Carfilzomib in Multiple Myeloma Cell Models
Document Type
Poster
Publication Date
3-2016
Abstract
modelsMultiple Myeloma is a widely spread malignancy with drug resistance being a major cause of therapeutic failure. NRF2 and p62 have been shown to contribute to resistance to Carfilzomib treatment in multiple myeloma. Carfilzomib is a second-generation proteasome inhibitor that is administered to patients with multiple myeloma who have failed several previous treatment regimens, including treatment with Bortezomib. Using in vitro cell models, we found NRF2 target genes to be activated in resistant cells. Elevated levels of the transcription factor NRF2 and the autophagy associated protein SQSTM1/p62 were found to be major contributors to this resistance and increased survival in the presence of Carfilzomib. We have shown that the mechanism of NRF2 activation involves elevated levels of its regulators PERK and p62. The proteosomal inhibition caused by Carfilzomib, causes an activation of PERK in the ER membrane. The PERK kinase directly phosphorylates NRF2 allowing it to activate. We also found that translation of NRF2 and p62 was more efficient in resistant cells. While NRF2 is translated using standard cap mediated initiation, p62 requires IRES mediation for it’s increased elevation. This transition is regulated by PERK kinase when it phosphorylates eIF2a. NRF2 is known to activate antioxidant defense, fatty acid oxidation (FAO), and autophagy. In our resistant cells we found decreased levels of reactive oxygen species, as well as elevated levels of both autophagy and fatty acid oxidation. Previously, we have shown that elevated levels of P62 cause resistance in other cell lines, and it appears to be a common element that is worth targeting in future research and treatment options. Along with the target of p62, small molecule mediated inhibition of NRF2 and PERK as well as inhibition of autophagy, FAO and cys transporter restores sensitivity to carfilzomib.
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Open Access
1
NRF2-P62 Contribute to Resistance to Carfilzomib in Multiple Myeloma Cell Models
modelsMultiple Myeloma is a widely spread malignancy with drug resistance being a major cause of therapeutic failure. NRF2 and p62 have been shown to contribute to resistance to Carfilzomib treatment in multiple myeloma. Carfilzomib is a second-generation proteasome inhibitor that is administered to patients with multiple myeloma who have failed several previous treatment regimens, including treatment with Bortezomib. Using in vitro cell models, we found NRF2 target genes to be activated in resistant cells. Elevated levels of the transcription factor NRF2 and the autophagy associated protein SQSTM1/p62 were found to be major contributors to this resistance and increased survival in the presence of Carfilzomib. We have shown that the mechanism of NRF2 activation involves elevated levels of its regulators PERK and p62. The proteosomal inhibition caused by Carfilzomib, causes an activation of PERK in the ER membrane. The PERK kinase directly phosphorylates NRF2 allowing it to activate. We also found that translation of NRF2 and p62 was more efficient in resistant cells. While NRF2 is translated using standard cap mediated initiation, p62 requires IRES mediation for it’s increased elevation. This transition is regulated by PERK kinase when it phosphorylates eIF2a. NRF2 is known to activate antioxidant defense, fatty acid oxidation (FAO), and autophagy. In our resistant cells we found decreased levels of reactive oxygen species, as well as elevated levels of both autophagy and fatty acid oxidation. Previously, we have shown that elevated levels of P62 cause resistance in other cell lines, and it appears to be a common element that is worth targeting in future research and treatment options. Along with the target of p62, small molecule mediated inhibition of NRF2 and PERK as well as inhibition of autophagy, FAO and cys transporter restores sensitivity to carfilzomib.
Comments
Presented at: GW Research Days 2016