Genome-Wide siRNA Screen for Modulators of Cell Death Induced by Proteasome Inhibitor Bortezomib

Chen, Siquan; Blank, Jonathan L.; Peters, Theodore; Liu, Xiaozhen J.; Rappoli, David M.; Pickard, Michael D.; Menon, Saurabh; Yu, Jie; Driscoll, Denise L.; Lingaraj, Trupti; Burkhardt, Anne L.; Chen, Wei; Garcia, Khristofer; Sappal, Darshan S.; Gray, Jesse; Hales, Paul; Leroy, Patrick; Ringeling, John; Rabino, Claudia; Spelman, James J.; Morgenstern, Jay P.; Lightcap, Eric S.

doi:10.1158/0008-5472.can-09-4428

Cited by 90 publications

(85 citation statements)

References 35 publications

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“…42 Interestingly, Asf1b is one of the proteins involved in the activity of bortezomib, although its precise function requires further validation. 43 Taken together, these results indicate that miR-214 interferes in the replication process of myeloma cells.…”

Section: Discussionmentioning

confidence: 75%

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

et al. 2012

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Section: Discussionmentioning

confidence: 75%

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

et al. 2012

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“…When used simultaneously, BI-D1870 showed limited additive effect in combination with currently available agents, such as bortezomib, adriamycin, and melphalan. Because c-MYC is required to realize cell death by bortezomib (40,41), it may be preferable to administer RSK2 inhibitor following bortezomib for effective myeloma cell killing. In this connection, our data showed no cross-resistance between bortezomib and RSK2 inhibitor, thus suggesting that drugs that target RSK2 Ser227 may be beneficial for eliminating residual myeloma cells following bortezomib exposure.…”

Section: Inhibition Of Rsk2mentioning

confidence: 99%

RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma

Shimura

Kuroda

et al. 2012

Molecular Cancer Therapeutics

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Multiple myeloma is an entity of cytogenetically and genetically heterogenous plasma cell neoplasms. Despite recent improvement in the treatment outcome of multiple myeloma by novel molecular-targeted chemotherapeutics, multiple myeloma remains incurable. The identification of a therapeutic target molecule in which various signaling for cell-survival converge is a core component for the development of new therapeutic strategies against multiple myeloma. RSK2 is an essential mediator of the ERK1/2 signaling pathway for cell survival and proliferation. In this study, we discovered that RSK2 Ser227 , which is located at the N-terminal kinase domain and is one site responsible for substrate phosphorylation, is activated through phosphorylation regardless of the type of cytogenetic abnormalities or upstream molecular signaling in all 12 multiple myeloma-derived cell lines examined and 6 of 9 patient-derived CD138-positive primary myeloma cells. The chemical inhibition of RSK2Ser227 by BI-D1870 or gene knockdown of RSK2 inhibits myeloma cell proliferation through apoptosis induction, and this anti-myeloma effect was accompanied by downregulation of c-MYC, cyclin D, p21 WAF1/CIP1 , and MCL1. RSK2 Ser227 inhibition resulting from BI-D1870 treatment restored lenalidomide-induced direct cytotoxicity of myeloma cells from interleukin-6-mediated cell protection, showed no cross-resistance to bortezomib, and exerted additive/synergistic antiproliferative effects in conjunction with the mTOR, histone deacetylase, and BH3-mimicking BCL2/BCLX L inhibitors. These results suggest that RSK2 Ser227 is a potential therapeutic target not only for newly diagnosed but also for patients with later phase multiple myeloma who are resistant or refractory to currently available anti-myeloma therapies.

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“…28 In addition, recent data showed that silencing individual proteasome genes including PSMA5 and PSMB2/3/7 sensitized multiple myeloma cells to bortezomib. 29,30 However, similar data in connection with PSMB1 is not reported thus far.…”

Section: Discussionmentioning

confidence: 64%

Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma

Varga

Mikala

Kiss

et al. 2017

Clinical Lymphoma Myeloma and Leukemia

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We retrospectively analyzed the prognostic impact of Proteasome subunit beta type 1 rs12717 polymorphism in 211 consecutively diagnosed multiple myeloma cases. Patients carrying the variant G allele showed significantly shorter progression free survival. In proteasomes of individuals with G/G genotype we found significantly reduced protease activity and lower inhibitory capacity of bortezomib on the caspase-and trypsin-like activity. 4Abstract Background: Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, an SNP with unknown functional effect, was recently reported to influence response to bortezomib based therapy in follicular lymphoma. Patients and Methods: We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results: On univariate analysis patients carrying the variant G allele showed significantly shorter progression free survival (PFS) with a pattern suggestive of a gene dose effect (PFS 26.4, 22.3,and 16.4 months in C/C, C/G, and G/G patients, respectively, p=0.002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (HR 2.29, p<0.001) with a similar trend in C/G carriers (HR 1.33, p=0.097) when compared to the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared to that of C/C carriers, despite the fact that the PSMB1 expression and the proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase-and trypsin-like activity of proteasomes from G/G individuals. Conclusion: Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes which are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanism to cope with the abundance of misfolded proteins.

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Genome-Wide siRNA Screen for Modulators of Cell Death Induced by Proteasome Inhibitor Bortezomib

Cited by 90 publications

References 35 publications

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma

Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma

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