The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma

• Published in: The Journal of biological chemistry 2015-12, Vol.290 (50), p.29854-29868
• Main Authors: Li, Bingzong, Fu, Jinxiang, Chen, Ping, Ge, Xueping, Li, Yali, Kuiatse, Isere, Wang, Hua, Wang, Huihan, Zhang, Xingding, Orlowski, Robert Z.
• Format: Article
• Language: English
• Subjects: all-trans-retinoic acid; animal model; bortezomib; Bortezomib - therapeutic use; Cell Line, Tumor; drug resistance; Drug Resistance, Neoplasm; Humans; Molecular Bases of Disease; Molecular Chaperones - physiology; multiple myeloma; Multiple Myeloma - drug therapy; NF-E2-Related Factor 2 - physiology; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); POMP; proteasome; Tretinoin - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.664953

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. Background: Acquired proteasome inhibitor resistance emerges in myeloma patients through incompletely understood mechanisms. Results: Activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and proteassemblin (POMP) was linked to bortezomib resistance, while their inhibition reversed resistance. Conclusion: The NRF2/POMP axis contributes to bortezomib resistance. Significance:NRF2/POMP axis inhibition can be translated to the clinic to reverse bortezomib resistance and induce chemosensitization.