The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma.
Resistance to the proteasome inhibitor bortezomib is an emerging clinical problem whose mechanisms have not been fully elucidated. We considered the possibility that this could be associated with enhanced proteasome activity in part through the action of the proteasome maturation protein (POMP). Bortezomib-resistant myeloma models were used to examine the correlation between POMP expression and bortezomib sensitivity. POMP expression was then modulated using genetic and pharmacologic approaches to determine the effects on proteasome inhibitor sensitivity in cell lines and in vivo models. Resistant cell lines were found to overexpress POMP, and while its suppression in cell lines enhanced bortezomib sensitivity, POMP overexpression in drug-naive cells conferred resistance. Overexpression of POMP was associated with increased levels of nuclear factor (erythroid-derived 2)-like (NRF2), and NRF2 was found to bind to and activate the POMP promoter. Knockdown of NRF2 in bortezomib-resistant cells reduced POMP levels and proteasome activity, whereas its overexpression in drug-naive cells increased POMP and proteasome activity. The NRF2 inhibitor all-trans-retinoic acid reduced cellular NRF2 levels and increased the anti-proliferative and pro-apoptotic activities of bortezomib in resistant cells, while decreasing proteasome capacity. Finally, the combination of all-trans-retinoic acid with bortezomib showed enhanced activity against primary patient samples and in a murine model of bortezomib-resistant myeloma. Taken together, these studies validate a role for the NRF2/POMP axis in bortezomib resistance and identify NRF2 and POMP as potentially attractive targets for chemosensitization to this proteasome inhibitor.
From the Department of Hematology, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China and the Departments of Lymphoma and Myeloma and.
Bingzong
B
Li
From the Department of Hematology, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China and.
Jinxiang
J
Fu
From the Department of Hematology, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China and.
Ping
P
Chen
From the Department of Hematology, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China and.
Xueping
X
Ge
From the Department of Hematology, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China and.
Yali
Y
Li
the Departments of Lymphoma and Myeloma and.
Isere
I
Kuiatse
the Departments of Lymphoma and Myeloma and.
Hua
H
Wang
the Departments of Lymphoma and Myeloma and.
Huihan
H
Wang
the Departments of Lymphoma and Myeloma and.
Xingding
X
Zhang
the Departments of Lymphoma and Myeloma and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 rorlowsk@mdanderson.org.
Robert Z
RZ
Orlowski
D000069286:Bortezomib / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D018832:Molecular Chaperones / Q000502:physiology*; D009101:Multiple Myeloma / Q000188:drug therapy*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
D018832:Molecular Chaperones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C413862:proteassemblin; D014212:Tretinoin; D000069286:Bortezomib
POMP; all-trans-retinoic acid; animal model; bortezomib; drug resistance; multiple myeloma; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); proteasome