PSMB5 is associated with proliferation and drug resistance in triple-negative breast cancer

Wei, Wensong; Yufeng, Zou; Jiang, Qi; Zhou, Zhengming; Ding, Haolong; Yan, Liping; Yang, Shi‐Ming

doi:10.5301/ijbm.5000283

Cited by 30 publications

(34 citation statements)

References 23 publications

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“…TNBC is known to be highly heterogeneous, so a bioinformatic approach was undertaken to more comprehensively evaluate the expression status of DYRK2; the DYRK2 substrate RPT3; and the proteasome core subunit, PSMB5, in TNBC diseased states. PSMB5, the core 20S proteasome subunit β5, harbors the chymotryptic-like activity of the proteasome and is known to be overexpressed and/or mutated in malignancy (10, 20–22). We mined the TCGA Cancer Genome Atlas (https://www.cancer.gov/); downloaded the gene expression data of all cancer types and matched normal tissue controls (where available); and compared DYRK2, RPT3, and PSMB5 gene expression ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Banerjee

Wei

Wang

et al. 2019

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

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Dependence on the 26S proteasome is an Achilles’ heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.

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Section: Resultsmentioning

confidence: 99%

Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Banerjee

Wei

Wang

et al. 2019

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

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“…Also the high activity of proteasome has been correlated with poor prognosis in TNBC patients and poor response to chemotherapy in vitro [ 42 ]. Proteasome inhibitors are under evaluation as new therapeutic options in TNBC patients [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…three-fold the dosage used in our in vivo protocol. In chemoresistant TNBC patients bortezomib achieved a partial response, followed by disease recurrence [ 42 ]. The novelty of our approach is the use of lower doses of chloroquine and bortezomib in combination with doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

Increasing intratumor C/EBP-β LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer

Salaroglio

Gazzano

Abdullrahman

et al. 2018

J Exp Clin Cancer Res

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BackgroundTriple negative breast cancer (TNBC) easily develops resistance to the first-line drug doxorubicin, because of the high levels of the drug efflux transporter P-glycoprotein (Pgp) and the activation of pro-survival pathways dependent on endoplasmic reticulum (ER). Interfering with these mechanisms may overcome the resistance to doxorubicin, a still unmet need in TNBC.MethodsWe analyzed a panel of human and murine breast cancer cells for their resistance to doxorubicin, Pgp expression, lysosome and proteasome activity, nitrite production, ER-dependent cell death and immunogenic cell death parameters. We evaluated the efficacy of genetic (C/EBP-β LIP induction) and pharmacological strategies (lysosome and proteasome inhibitors), in restoring the ER-dependent and immunogenic-dependent cell death induced by doxorubicin, in vitro and in syngeneic mice bearing chemoresistant TNBC. The results were analyzed by one-way analysis of variance test.ResultsWe found that TNBC cells characterized by high levels of Pgp and resistance to doxorubicin, had low induction of the ER-dependent pro-apoptotic factor C/EBP-β LIP upon doxorubicin treatment and high activities of lysosome and proteasome that constitutively destroyed LIP. The combination of chloroquine and bortezomib restored doxorubicin sensitivity by activating multiple and interconnected mechanisms. First, chloroquine and bortezomib prevented C/EBP-β LIP degradation and activated LIP-dependent CHOP/TRB3/caspase 3 axis in response to doxorubicin. Second, C/EBP-β LIP down-regulated Pgp and up-regulated calreticulin that triggered the dendritic cell (DC)-mediated phagocytosis of tumor cell, followed by the activation of anti-tumor CD8+T-lymphocytes upon doxorubicin treatment. Third, chloroquine and bortezomib increased the endogenous production of nitric oxide that further induced C/EBP-β LIP and inhibited Pgp activity, enhancing doxorubicin’s cytotoxicity. In orthotopic models of resistant TNBC, intratumor C/EBP-β LIP induction - achieved by a specific expression vector or by chloroquine and bortezomib - effectively reduced tumor growth and Pgp expression, increased intra-tumor apoptosis and anti-tumor immune-infiltrate, rescuing the efficacy of doxorubicin.ConclusionsWe suggest that preventing C/EBP-β LIP degradation by lysosome and proteasome inhibitors triggers multiple virtuous circuitries that restore ER-dependent apoptosis, down-regulate Pgp and re-activate the DC/CD8+T-lymphocytes response against TNBC. Lysosome and proteasome inhibitors associated with doxorubicin may overcome the resistance to the drug in TNBC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0967-0) contains supplementary material, which is available to authorized users.

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“…The PSMB family has many members, such as PSMB5, which is involved in tumor progression and immunosuppression . The tumor‐promoting role of PSMB5 has been widely demonstrated in various human cancers, including PCa, and takes part in many processes of tumor development, including growth, metastasis, and drug resistance .…”

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confidence: 99%

Transcriptional downregulation of miR‐127‐3p by CTCF promotes prostate cancer bone metastasis by targeting PSMB5

Fan

Zhang

et al. 2019

FEBS Letters

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Prostate cancer (PCa) is one of the most common cancers in males and particularly tends to metastasize to bone. Currently, metastatic bone disease is incurable, and new therapies need to be developed. Our study aims to determine the role of miR‐127‐3p in PCa metastasis to bone. The results demonstrate that miR‐127‐3p is markedly reduced in bone metastasis‐positive PCa tissues relative to that in bone metastasis‐negative PCa tissues. Furthermore, overexpressing miR‐127‐3p inhibits PCa cell invasion and migration in vitro by targeting the proteasome β‐subunit PSMB5. Moreover, CCCTC‐binding factor (CTCF) transcriptionally inhibits miR‐127‐3p by interacting with the miR‐127‐3p promoter. Collectively, this study uncovers a novel mechanism of the CTCF/miR‐127‐3p/PSMB5 axis in promoting PCa bone metastasis, indicating that miR‐127‐3p could function as a promising therapeutic target against bone metastasis.

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PSMB5 is associated with proliferation and drug resistance in triple-negative breast cancer

Abstract: Our results suggest a potential role for PSMB5 as a biomarker and therapeutic target for TNBC.

Cited by 30 publications

References 23 publications

Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Increasing intratumor C/EBP-β LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer

Transcriptional downregulation of miR‐127‐3p by CTCF promotes prostate cancer bone metastasis by targeting PSMB5

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