The role of ubiquitin-specific protease 14 (USP14) in cell adhesion-mediated drug resistance (CAM-DR) of multiple myeloma cells

2016 ◽  
Vol 98 (1) ◽  
pp. 4-12 ◽  
Author(s):  
Xiaohong Xu ◽  
Jing Liu ◽  
Chaoyan Shen ◽  
Linlin Ding ◽  
Fei Zhong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Myeloma Cells ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

scholarly journals EphA4 promotes cell proliferation and cell adhesion–mediated drug resistance via the AKT pathway in multiple myeloma

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769429 ◽  
Author(s):  
Linlin Ding ◽  
Yaodong Shen ◽  
Jing Ni ◽  
Yiqing Ou ◽  
Yangyu Ou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Akt Pathway ◽  
Cyclin Dependent Kinase ◽  
Myeloma Cells ◽  
Eph Receptor ◽  
Regulation Of Cell Cycle ◽  
Cyclin Dependent Kinase 5

Eph receptor A4 (EphA4), a member of the erythropoietin-producing hepatocellular (Eph) family, has been reported to upregulate in several tumors. However, the role of EphA4 in multiple myeloma has not been clarified yet. In this study, we found that EphA4 promoted proliferation of multiple myeloma cells via the regulation of cell cycle. Besides, EphA4 was closely related to cell adhesion of multiple myeloma cells and promoted cell adhesion–mediated drug resistance by enhancing the phosphorylation levels of Akt (p-AKT) expression in multiple myeloma. More interestingly, we discovered that EphA4 can interact with cyclin-dependent kinase 5 (CDK5) and regulate its expression in multiple myeloma. CDK5 has been reported to be overexpressed in multiple myeloma which mediated bortezomib resistance and also participated in AKT pathway. And we have also proved the fact. So, we supposed that EphA4 interacted with CDK5 and promoted its expression which in turn enhanced p-AKT expression and promoted cell adhesion–mediated drug resistance in multiple myeloma. Therefore, this study clarifies the molecular mechanism of cell adhesion–mediated drug resistance and may be useful in identifying potential target for treatment of multiple myeloma.

Abstract 5686: Engineering multifunctional nanoparticles to selectively target multiple myeloma cells and overcome cell adhesion-mediated drug resistance

2012 ◽  
Author(s):  
Tanyel Kiziltepe ◽  
Jonathan D. Ashley ◽  
Jared F. Stefanick ◽  
Nathan J. Alves ◽  
Micheal W. Handlogten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Multifunctional Nanoparticles ◽  
Myeloma Cells

scholarly journals Erratum: Corrigendum: The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xin Wang ◽  
Magdalena Mazurkiewicz ◽  
Ellin-Kristina Hillert ◽  
Maria Hägg Olofsson ◽  
Stefan Pierrou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myeloma Cells ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

scholarly journals ANXA7 promotes the cell cycle, proliferation and cell adhesion-mediated drug resistance of multiple myeloma cells by up-regulating CDC5L

Aging ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 11100-11115 ◽  
Author(s):  
Haiyan Liu ◽  
Dan Guo ◽  
Yuou Sha ◽  
Chenlu Zhang ◽  
Yijing Jiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Myeloma Cells

Influence of Targeted Therapy in Redefining High-Risk Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-7-sci-7
Author(s):  
Lori Hazlehurst ◽  
William S. Dalton ◽  
Danielle Yarde ◽  
Yulia Nefedova ◽  
Dmitry Gabrilovich
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Cell Adhesion ◽  
Tumor Microenvironment ◽  
Residual Disease ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Acquired Drug Resistance

Abstract Multiple myeloma is a disease that typically responds to initial treatment; however, the disease is not cured by chemotherapy, and drug resistance ultimately develops. Most studies investigating the problem of drug resistance have focused on acquired resistance or resistance that occurs after response to prior therapy as a result of residual disease. Intrinsic factors, such as reduced drug uptake, enhanced damage response (i.e., DNA repair), altered drug metabolism, or inhibition of programmed cell death pathways are known to contribute to acquired drug resistance. For example, it was recently reported that the acquired melphalan resistant phenotype in myeloma cell lines was associated with over-expression of the Fanconi anemia (FA)/BRCA pathway genes. Enhanced interstrand cross-link (ICL) repair via the FA/BRCA pathway was causally related to melphalan resistance and disruption of this pathway using knock-down techniques reversed drug resistance. Furthermore, bortezomib (Velcade) has been reported to enhance melphalan treatment, and recent pre-clinical data has shown that bortezomib reduces FA/BRCA gene expression and function. Clinical trials are necessary to determine the role of the FA/ BRCA pathway in acquired drug resistance for myeloma patients and whether targeting this pathway enables prevention of or the ability to overcome acquired melphalan resistance in myeloma patients. Conversely, factors that promote tumor cell survival and drug resistance that are external to the tumor cell itself might exist. Evidence supporting the importance of understanding the influence of the tumor microenvironment on drug sensitivity has been reported by several investigators. The tumor microenvironment for hematologic malignancies, including myeloma, is principally the bone marrow. The bone marrow contains candidate components that contribute to reduced drug activity, minimal residual disease, and emergence of drug resistant cells. Cell adhesion molecules expressed by myeloma cells, including the β integrins, bind to fibronectin and other extracellular matrix components of the bone marrow, and this interaction contributes to a reversible, de novo drug resistance phenotype called “cell adhesion mediated drug resistance” or CAMDR. Adhesion via integrins is known to activate a network of signal transduction pathways that influence cell survival, growth, and differentiation. Several targets that are influenced by integrin adhesion and may contribute to CAM-DR include the following: reduced proapoptotic Bim levels, alterations in nuclear topoisomerase II levels, increased p27 kip1 levels, and changes in FLIP1 levels. In addition, myeloma cell adhesion to bone marrow stroma (BMS) involves other adhesion molecules and signaling events that promote CAMDR. For example, Notch1 receptors expressed on multiple myeloma cells when stimulated by Jagged causes growth arrest and protection from drug-induced apoptosis. Recently, approaches to inhibit integrin and Notch signaling associated with CAM-DR have been examined pre-clinically. Clinical trials are necessary to determine if these approaches will prevent or overcome CAM-DR in patients.

scholarly journals The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xin Wang ◽  
Magdalena Mazurkiewicz ◽  
Ellin-Kristina Hillert ◽  
Maria Hägg Olofsson ◽  
Stefan Pierrou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Uptake ◽  
Myeloma Cells ◽  
Bcl2 Family ◽  
Promising Strategy ◽  
Specific Protease ◽  
Xenograft Models ◽  
Ubiquitin Specific Protease ◽  
Extended Survival

Abstract Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.

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