Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling

Zhang, Xingding; Baladandayuthapani, Veerabhadran; Lin, Heather; Mulligan, George; Li, Bin; Esseltine, Dixie Lee; Qi, Lin; Xu, Jiegou; Hunziker, Walter; Barlogie, Bart; Usmani, Saad Z.; Zhang, Qing; Crowley, John; Hoering, Antje; Shah, Jatin J.; Weber, Donna M.; Manasanch, Elisabet E.; Thomas, Sheeba K.; Li, Bing Zong; Wang, Hui Han; Zhang, Jiexin; Kuiatse, Isere; Tang, Jessica; Wang, Hua; He, Jin; Yang, Jing; Milan, Enrico; Cenci, Simone; Wen, Chen; Wang, Zhi Qiang; Davis, R. Eric; Yang, Lin; Orłowski, Robert Z.

doi:10.1016/j.ccell.2016.03.026

Cited by 87 publications

(90 citation statements)

References 37 publications

(49 reference statements)

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“…In summary, our finding of noncanonical SQSTM1/p62-Nrf2 pathway activation adds to the growing appreciation from our work and others that carfilzomib resistance in MM can arise via multiple mechanisms [10, 11, 65, 85, 99]. MM is heterogeneous in its etiology and progression so these varied results are not entirely unexpected [100].…”

Section: Discussionmentioning

confidence: 51%

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

et al. 2016

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Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiation factor gene EIF4E3 was among the Nrf2 target genes upregulated in LP-1/Cfz cells, suggesting existence of a positive feedback loop. In line with this, we found that siRNA knockdown of eIF4E3 decreased Nrf2 protein levels. On the other hand, elevated SQSTM1/p62 levels were due at least in part to activation of the PERK-eIF2α pathway. LP-1/Cfz cells had decreased levels of reactive oxygen species as well as elevated levels of fatty acid oxidation and prosurvival autophagy. Genetic and pharmacologic inhibition of the Nrf2-EIF4E3 axis or the PERK-eIF2α pathway, disruption of redox homeostasis or inhibition of fatty acid oxidation or autophagy conferred sensitivity to carfilzomib. Our findings were supported by clinical data where increased EIF4E3 expression was predictive of Nrf2 target gene upregulation in a subgroup of patients with chemoresistant minimal residual disease and relapsed/refractory MM. Thus, our data offer a preclinical rationale for including inhibitors of the SQSTM1/p62-Nrf2 pathway to the treatment regimens for certain advanced stage MM patients.

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Section: Discussionmentioning

confidence: 51%

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

et al. 2016

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“…Finally, the authors of a study published in 2016 127 reported that the expression levels of tight junction protein 1 (ZO-1) are strongly and directly associated with high sensitivity to bortezomib in both myeloma and MCL cell line models and primary myeloma cells 128 . Interestingly, the downstream mechanism implicated in sensitivity was activation of EGFR signaling, which enhanced the levels of proteasome subunit synthesis in a signal transducer and activator of transcription 3 (STAT3)-dependent manner 127 .…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibitors in cancer therapy

2017

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The ubiquitin proteasome pathway was discovered in the 1980s to be a central component of the cellular protein degradation machinery with essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins. Cancer cells produce proteins that promote both cell survival and proliferation, and/or inhibit mechanisms of cell death. This notion set the stage for preclinical testing of proteasome inhibitors as a means to shift this fine equilibrium towards cell death. Since the late 1990s, clinical trials have been conducted for a variety of malignancies, leading to regulatory approvals of proteasome inhibitors to treat multiple myeloma and mantle cell lymphoma. First-generation and second-generation proteasome inhibitors can elicit deep initial responses in patients with myeloma, in whom these drugs have dramatically improved outcomes, but relapses are frequent and acquired resistance to treatment eventually emerges. In addition, promising preclinical data obtained with proteasome inhibitors in models of solid tumours have not been confirmed in the clinic, indicating a role for primary resistance. Investigation of the mechanisms of resistance is, therefore, essential to further maximize the utility of this class of drugs in the era of personalized medicine. Herein, we discuss the advances and challenges resulting from the introduction of proteasome inhibitors into the clinic.

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“…In terms of clinical relevance, however, such mutations have yet to be detected in clinical samples (13). Additional mechanisms of resistance include alteration of specific cellular pathways such as constitutive activation of NF-κB (14), activation of the chaperone machinery (15,16), or alterations in the EGFR/JAK1/ STAT3 pathway (17).…”

mentioning

confidence: 99%

Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers

Tsvetkov

Sokol

Jin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The use of proteasome inhibitors to target cancer’s dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers.

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Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling

Cited by 87 publications

References 37 publications

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

Proteasome inhibitors in cancer therapy

Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers

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