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

scholarly journals Elucidating the expression and function of Numbl during cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM)

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yuejiao Huang ◽  
Xianting Huang ◽  
Chun Cheng ◽  
Xiaohong Xu ◽  
Hong Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Clinical Problem ◽  
Integrin Β1 ◽  
Cell Viability Assay ◽  
Adhesion Model

Abstract Background Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin β1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development. Methods Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinβ1 expression by Western Blot analysis. The interaction between Numbl and Integrinβ1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis. Results Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin β1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin β1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin β1 promotes the formation of CAM-DR in MM cells. Conclusions Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.

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

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.

Pyk2 Mediates Enhanced STAT3 Phosphorylation Following Collaborative Signaling Between gp130 and beta1 Integrins in Adhered Myeloma and B Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2895-2895
Author(s):  
Mark B Meads ◽  
Liang Nong ◽  
Linda Mathews ◽  
William S. Dalton ◽  
Kenneth H. Shain
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Tumor Cells ◽  
Kinase Activity ◽  
Therapy Resistance ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Cycle Arrest ◽  
Stat3 Signaling

Abstract Abstract 2895 Multiple myeloma is the second most common hematologic malignancy and remains incurable due to the eventual development of drug resistance. Therapy resistance has been linked to both acquired genetic changes as well as the dynamic influences of soluble and physical factors present in the microenvironment. We and others have shown that adhesion of tumor cells to the extracellular matrix component fibronectin (FN) via integrins leads to cell cycle arrest and protection from chemotherapy or Cell Adhesion-Mediated Drug Resistance (CAM-DR). The pleiotropic cytokine IL-6 has also been shown to mediate drug resistance in both solid and hematopoietic tumors [1]. To date, the influence of these two effectors on drug resistance has been studied separately; however, within the context of the bone marrow myeloma cells are influenced by both soluble and physical effectors of the microenvironment simultaneously. Using a reductionist model of the multivariant microenvironment, we recently demonstrated that unique collaborative signaling between FN-adhered cells and IL-6 leads to increased proliferation of protected tumor cells and a more malignant phenotype[2]. Our results demonstrate the FN-adhesion mediated cell-cycle arrest of myeloma cells was reversed following stimulation of adhered cells with IL-6. This phenotype was associated with a novel amplification of IL-6-induced STAT3 activation in adhered cells [2]. To further characterized the molecular events mediating this unique event we focused on the focal adhesion kinase, Proline-rich tYrosine Kinase 2 (Pyk2/FAK2). Pyk2 is a downstream intermediate of integrin signaling and has been demonstrated to amplify EGFR and cSrc-induced STAT3 activation. As such, we hypothesized that Pyk2 may be an important modulator of the enhanced STAT3 activation following multivariant signaling between beta1 integrins and gp130[3]. Our results link this amplification to Pyk2 in myeloma and murine pro-B cell lines. Western blot analysis demonstrated that Pyk2 autophophorylation on tyrosine 402 is induced following myeloma cell adhesion to FN correlating with the amplification of IL-6-induced STAT3, JAK1, and gp130 phosphorylation in both myeloma and pro B cell line models. Targeting Pyk2 with RNA interference attenuated the adhesion-associated amplification of STAT3 signaling as well as JAK1 and gp130 phosphorylation, but did not influence the limited STAT3 activation in cells grown in suspension. Further we demonstrated that Pyk2 kinase activity was similarly required for the activation of JAK1/STAT3 signaling under collaborative conditions, but not by IL-6 alone. Consistent with previous results ERK1/2 and Akt signaling were not affected by Pyk2 siRNA or kinase activity. Importantly, Pyk2 siRNA did not inhibit myeloma cell adhesion (n=4, p-value >0.05). Our previous results demonstrated that that the enhanced STAT3 signaling involved a FN-adhesion specific binding of unphosphorylated STAT3 with gp130 (independent of IL-6 stimulation). To determine if Pyk2 was similarly recruited to gp130 under co-stimulatory conditions we have initially used confocal microscopy. Confocal imaging with antisera to Pyk2 and gp130 demonstrated colocalization of the two effectors upon adhesion of myeloma cell to FN, but not in those grown in suspension. These data demonstrate that within the context of multivariant stimulation (IL-6 and FN-adhesion) a unique Pyk2-mediated JAK1/STAT3 signaling cascade is associated with unique biologic sequelae. We are currently exploring the biological sequelae of Pyk2-mediated collaborative signaling between integrins and IL-6. Key endpoints currently under investigation include proliferation and drug-response. These findings are significant because they suggests strategies targeting Pyk2 could be used to block cooperative signaling between integrins and IL-6, and inhibit the proliferation and/or therapy resistance conferred to tumor cells by the multivariant bone marrow niche. Disclosures: No relevant conflicts of interest to declare.

Survivin Expression, Regulation and Biological Role in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1420-1420
Author(s):  
Mathilde Romagnoli ◽  
Régis Bataille ◽  
Sophie Barillé-Nion
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Survivin Expression ◽  
Drug Induced ◽  
Myeloma Cells ◽  
Stable Transfectants

Abstract Multiple myeloma (MM) is characterized by the accumulation within the bone marrow of malignant plasma cells with an enhanced survival capacity. Myeloma cells often develop drug resistance leading to treatment failure in patients. Survivin is a member of the inhibitor of apoptosis (IAP) gene family that has been implicated in both cell viability and regulation of mitosis in cancer cells. In this study, we have evaluated survivin expression and its biological involvement in viability, proliferation, cell cycle and drug resistance in myeloma cells. First by western blotting we detected survivin expression in 17 human myeloma cell lines (HMCL) from moderate level in the HMCL XG6 to strong level in the HMCL U266. Survivin was also detectable in primary myeloma cells purified from blood or bone marrow samples of 20 patients in contrast to purified B lymphocytes from tonsil samples or autologous EBV infected B lymphocytes. Survivin expression peaked at G2/M phase as obtained by drug-induced cell-cycle arrest. Second, we demonstrated that both major myeloma growth factors, IL-6 and IGF-1, induced upregulation of survivin expression through JAK/STAT and PI3K/AKT signalling pathways. In order to elucidate survivin role in myeloma cells, we established XG6 stable transfectants overexpressing survivin and extinguished survivin expression by siRNA in U266. Preliminary data suggest that survivin may participate in spontaneous cell death regulation, cell proliferation and drug sensitivity in those HMCL. In summary, our findings tend to show that survivin may be playing an important role in the pathogenesis of MM. A more defined understanding of survivin biology should enhance the rational development of drugs to inhibit its function in myeloma cells.

Wnt3/RhoA/ROCK Signaling Pathway Is Involved in VLA6-Dependent Adhesion-Mediated Drug Resistance of Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2518-2518
Author(s):  
Masayoshi Kobune ◽  
Yutaka Kawano ◽  
Rishu Takimoto ◽  
Takuya Matsunaga ◽  
Junji Kato ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Stromal Cells ◽  
Critical Role ◽  
Rho Kinase ◽  
Myeloma Cell ◽  
Myeloma Cells

Abstract Adhesion of myeloma cells to BM stromal cells is now considered to play a critical role in chemo-resistance. However, little is known about the molecular mechanism of cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma. In this study, we focused on relationship between drug resistance and expression of Wnts, the factor regulating the cell adhesion and proliferation, in myeloma cells. To gain insight into involvement of Wnt signaling in CAM-DR, we first screened the expression of Wnt family in myeloma cell lines (RPMI8226, ARH77, KMS-5 and MM1S) by reverse transcription-polymerase chain reaction analysis. Although the mRNAs of Wnt2b, Wnt7a and Wnt10b were variably expressed in some of myeloma cell lines, Wnt3 mRNA was detected in all the myeloma cells examined. KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human BM stromal cells and accumulation of β-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPMI8226 and MM1S, which modestly expressed Wnt3 protein, rather weakly adhered to human BM stromal cells. We then examined the relevance of Wnt3 expression to adhesive property to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited apparent CAM-DR against Doxorubicin. This CAM-DR was significantly reduced by anti-integrinβ1 antibody, anti- integrinα6 antibody and a Wnt-receptor competitor, secreted Frizzled related protein-1 and Rho kinase inhibitor (Y27632 and OH-fasudil), but not by the specific inhibitor of canonical signaling (DKK-1), indicating that Wnt-mediated CAM-DR which is dependent on integrinα6/β1 (VLA-6)-mediated attachment to stromal cells is induced by Wnt/RhoA-Rho kinase (ROCK) pathway signal. This CAM-DR for doxorubicin was also significantly reduced by Wnt3 siRNA transfer to KMS-5 and further augmented by addition of Wnt3 conditioned medium. These results indicate that Wnt3 contributes to VLA-6-mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma cells. Thus, the Wnt3/RhoA/ROCK signaling pathway could be a promising molecular target to overcome CAM-DR.

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