COMPENSATORY STRESS PATHWAYS IN MODULATING ER STRESS IN BORTEZOMIB RESISTANT MULTIPLE MYELOMA.
(Abstract release date: 05/19/16)
EHA Library. Nikesitch N. 06/09/16; 132808; E1259
Mr. Nicholas Nikesitch
Contributions
Contributions
Abstract
Abstract: E1259
Type: Eposter Presentation
Background
Multiple myeloma (MM) remains a predominantly incurable malignancy despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Nonetheless, proteasome inhibitors (PI) such Bortezomib (Bz) have been effective in treating the disease to date. The 26S proteasome inhibitor indirectly targets the unfolded protein response (UPR) by inhibiting proteasomal degradation of ubiquitinated paraprotein, subsequently leading to the lethal accumulation of paraprotein within the cell. Initial treatment is effective, however most patients eventually develop resistance to the drug. The mechanism of resistance is still unknown, though one possible mechanism contributing to Bz resistance could be chaperone-mediated autophagy (CMA). Upregulated in a number of tumours, CMA specifically targets and degrades soluble cytosolic proteins. It is therefore likely that this pathway could be an alternative stress management pathway in Bz resistance.
Aims
We aimed to assess CMA in sensitive and resistant MM, and its role in alleviating ER stress in bortezomib resistance.
Methods
QPCR, western blotting, cell viability assays, ER imaging and shRNA assays were performed to assess the role and importance of UPR and autophagy in Bz resistant MM, and was correlated to Bz sensitivity.
Results
Molecularly and morphologically, we identified reduced UPR activity as a result of increasing Bz resistance in both resistant MM patients and in resistant KMS11 cells. We further identified that the chaperone-mediated autophagy (CMA) marker, LAMP2A, was highly expressed in resistant cells compared to sensitive cells in cell lines and patients. CMA activity was also seen to increase in 4 different MM cell lines under various levels of ER induced stress, strongly suggesting the pathways importance in ER stress management. Upon further investigation, preliminary data has also shown that macroautophagy may provide as a compensatory mechanism in cells with impaired CMA.
Conclusion
CMA is upregulated in Bz resistant MM and functions as a compensatory stress mechanism in alleviating ER stress in cells with reduced UPR activity. Partial inhibition of the pathway subsequently results in the activation of macroautophagy. To effectively treat MM and potentially overcome Bz resistance, new therapies targeting autophagy are required.
Session topic: E-poster
Keyword(s): Bortezomib, Molecular, Myeloma, Resistance
Type: Eposter Presentation
Background
Multiple myeloma (MM) remains a predominantly incurable malignancy despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Nonetheless, proteasome inhibitors (PI) such Bortezomib (Bz) have been effective in treating the disease to date. The 26S proteasome inhibitor indirectly targets the unfolded protein response (UPR) by inhibiting proteasomal degradation of ubiquitinated paraprotein, subsequently leading to the lethal accumulation of paraprotein within the cell. Initial treatment is effective, however most patients eventually develop resistance to the drug. The mechanism of resistance is still unknown, though one possible mechanism contributing to Bz resistance could be chaperone-mediated autophagy (CMA). Upregulated in a number of tumours, CMA specifically targets and degrades soluble cytosolic proteins. It is therefore likely that this pathway could be an alternative stress management pathway in Bz resistance.
Aims
We aimed to assess CMA in sensitive and resistant MM, and its role in alleviating ER stress in bortezomib resistance.
Methods
QPCR, western blotting, cell viability assays, ER imaging and shRNA assays were performed to assess the role and importance of UPR and autophagy in Bz resistant MM, and was correlated to Bz sensitivity.
Results
Molecularly and morphologically, we identified reduced UPR activity as a result of increasing Bz resistance in both resistant MM patients and in resistant KMS11 cells. We further identified that the chaperone-mediated autophagy (CMA) marker, LAMP2A, was highly expressed in resistant cells compared to sensitive cells in cell lines and patients. CMA activity was also seen to increase in 4 different MM cell lines under various levels of ER induced stress, strongly suggesting the pathways importance in ER stress management. Upon further investigation, preliminary data has also shown that macroautophagy may provide as a compensatory mechanism in cells with impaired CMA.
Conclusion
CMA is upregulated in Bz resistant MM and functions as a compensatory stress mechanism in alleviating ER stress in cells with reduced UPR activity. Partial inhibition of the pathway subsequently results in the activation of macroautophagy. To effectively treat MM and potentially overcome Bz resistance, new therapies targeting autophagy are required.
Session topic: E-poster
Keyword(s): Bortezomib, Molecular, Myeloma, Resistance
Abstract: E1259
Type: Eposter Presentation
Background
Multiple myeloma (MM) remains a predominantly incurable malignancy despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Nonetheless, proteasome inhibitors (PI) such Bortezomib (Bz) have been effective in treating the disease to date. The 26S proteasome inhibitor indirectly targets the unfolded protein response (UPR) by inhibiting proteasomal degradation of ubiquitinated paraprotein, subsequently leading to the lethal accumulation of paraprotein within the cell. Initial treatment is effective, however most patients eventually develop resistance to the drug. The mechanism of resistance is still unknown, though one possible mechanism contributing to Bz resistance could be chaperone-mediated autophagy (CMA). Upregulated in a number of tumours, CMA specifically targets and degrades soluble cytosolic proteins. It is therefore likely that this pathway could be an alternative stress management pathway in Bz resistance.
Aims
We aimed to assess CMA in sensitive and resistant MM, and its role in alleviating ER stress in bortezomib resistance.
Methods
QPCR, western blotting, cell viability assays, ER imaging and shRNA assays were performed to assess the role and importance of UPR and autophagy in Bz resistant MM, and was correlated to Bz sensitivity.
Results
Molecularly and morphologically, we identified reduced UPR activity as a result of increasing Bz resistance in both resistant MM patients and in resistant KMS11 cells. We further identified that the chaperone-mediated autophagy (CMA) marker, LAMP2A, was highly expressed in resistant cells compared to sensitive cells in cell lines and patients. CMA activity was also seen to increase in 4 different MM cell lines under various levels of ER induced stress, strongly suggesting the pathways importance in ER stress management. Upon further investigation, preliminary data has also shown that macroautophagy may provide as a compensatory mechanism in cells with impaired CMA.
Conclusion
CMA is upregulated in Bz resistant MM and functions as a compensatory stress mechanism in alleviating ER stress in cells with reduced UPR activity. Partial inhibition of the pathway subsequently results in the activation of macroautophagy. To effectively treat MM and potentially overcome Bz resistance, new therapies targeting autophagy are required.
Session topic: E-poster
Keyword(s): Bortezomib, Molecular, Myeloma, Resistance
Type: Eposter Presentation
Background
Multiple myeloma (MM) remains a predominantly incurable malignancy despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Nonetheless, proteasome inhibitors (PI) such Bortezomib (Bz) have been effective in treating the disease to date. The 26S proteasome inhibitor indirectly targets the unfolded protein response (UPR) by inhibiting proteasomal degradation of ubiquitinated paraprotein, subsequently leading to the lethal accumulation of paraprotein within the cell. Initial treatment is effective, however most patients eventually develop resistance to the drug. The mechanism of resistance is still unknown, though one possible mechanism contributing to Bz resistance could be chaperone-mediated autophagy (CMA). Upregulated in a number of tumours, CMA specifically targets and degrades soluble cytosolic proteins. It is therefore likely that this pathway could be an alternative stress management pathway in Bz resistance.
Aims
We aimed to assess CMA in sensitive and resistant MM, and its role in alleviating ER stress in bortezomib resistance.
Methods
QPCR, western blotting, cell viability assays, ER imaging and shRNA assays were performed to assess the role and importance of UPR and autophagy in Bz resistant MM, and was correlated to Bz sensitivity.
Results
Molecularly and morphologically, we identified reduced UPR activity as a result of increasing Bz resistance in both resistant MM patients and in resistant KMS11 cells. We further identified that the chaperone-mediated autophagy (CMA) marker, LAMP2A, was highly expressed in resistant cells compared to sensitive cells in cell lines and patients. CMA activity was also seen to increase in 4 different MM cell lines under various levels of ER induced stress, strongly suggesting the pathways importance in ER stress management. Upon further investigation, preliminary data has also shown that macroautophagy may provide as a compensatory mechanism in cells with impaired CMA.
Conclusion
CMA is upregulated in Bz resistant MM and functions as a compensatory stress mechanism in alleviating ER stress in cells with reduced UPR activity. Partial inhibition of the pathway subsequently results in the activation of macroautophagy. To effectively treat MM and potentially overcome Bz resistance, new therapies targeting autophagy are required.
Session topic: E-poster
Keyword(s): Bortezomib, Molecular, Myeloma, Resistance
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