scholarly journals Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model

Oncotarget ◽  
2013 ◽  
Vol 5 (3) ◽  
pp. 634-648 ◽  
Author(s):  
Kodappully Sivaraman Siveen ◽  
Nurulhuda Mustafa ◽  
Feng Li ◽  
Radhamani Kannaiyan ◽  
Kwang Seok Ahn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Gene Products ◽  
Xenograft Mouse Model ◽  
Anticancer Effects

scholarly journals NEK2 Promotes Bortezomib Resistance through Enhancing Autophagy By Upregulation of Beclin1 in Multiple Myeloma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4332-4332
Author(s):  
Jiliang Xia ◽  
Yanjuan He ◽  
Bin Meng ◽  
Jingyu Zhang ◽  
Xuan Wu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Mouse Model ◽  
Protein Level ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Transcriptional Level ◽  
Newly Diagnosed ◽  
Multidrug Resistance Proteins ◽  
Xenograft Mouse Model

Background: Multiple Myeloma(MM) is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant of plasma cells in the bone microenvironment, and monoclonal protein in the blood or urine. Drug resistance is one of the main causes of cancer relapse, thus exploring the molecular mechanisms of drug resistance is important for improving therapeutic effect in MM. Our previous publications have demonstrated NEK2 mediated drug resistance via up-regulation of multidrug resistance proteins. In this study, we found autophagy was involved in NEK2 induced Bortezomib resistance in MM cells. Materials and Methods: Primary CD138 positive cells derived from healthy donors(n=6), newly diagnosed MM patients(n=9) and relapsed MM patients(n=7) were isolated by using beads conjugated with human CD138 antibody. Immunofluorescence was performed to detect the expression of NEK2 and LC3B(LC3B-Ⅰand LC3B-Ⅱ) in primary CD138 positive cells. DALGreen was used to detect autolysosome in MM cells. TAP-MS and CO-IP were used to analyze NEK2 interacting proteins. Cell proliferation were examined with soft agar colony formation and cell count. Cell apoptosis was tested through detecting cleaved Caspase3 and cleaved PARP by western blot. Xenograft mouse model of MM were prepared by subcutaneous injection of MM cells(KMS11 NEK2 OE+Scramble, KMS11 NEK2 OE+Beclin1 sh) into immunodeficient B-NDG mouse(1×106 cell/mice). Results: Firstly, immunofluorescence results showed NEK2 expression and LC3B-Ⅱ labeled autophagosome were significantly increased in CD138 positive cells derived from relapsed MM patients as compared with newly diagnosed MM patients and HD. Moreover, over-expression of NEK2 enhanced antophagy, while knockdown of NEK2 suppressed autophagy in MM cells. To explore the underling mechanisms of NEK2 induces autophagy in MM cells, TAP-MS was performed. As a result, Beclin1, an important regulatory protein of autophagy, was identified as NEK2 interacting protein, which was further confirmed by CO-IP in MM cell lines KMS11 and RPMI 8226. Additionally, we found that NEK2 regulated the expression of Beclin1 at protein level, but not at transcriptional level. Subsequent mechanism study indicated NEK2 increased the stability of Beclin1 protein through USP7 mediated deubiquitination, thereby promoting the formation of the Beclin1-Vps15-Vps34 complex, and finally, enhancing autophagy in MM cells. Furthermore, knockdown of Beclin1 significantly suppressed NEK2 induced autophagy in MM cells. Alternatively, down-regulation of Beclin1 overcame NEK2 mediated Bortezomib resistance in xenograft mouse model of MM , suggesting that targeting Beclin1 is a promising approach to therapy MM patients with high NEK2 expression. Conclusion: Our findings revealed NEK2 induced autophagy through up-regulation of Beclin1 at protein level, and confirmed autophagy was involved in NEK2 mediated Bortezomib resistance in MM. Taken together, this study provided novel insight into treating relapsed MM patients. Disclosures No relevant conflicts of interest to declare.

Depletion of Host CD122+ Cells Facilitates Widespread Skeletal Multiple Myeloma Engraftment in NOD/SCID Recipients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2734-2734
Author(s):  
Lisa M Freeman ◽  
Eugene Petcu ◽  
Robert Smith ◽  
Ali Salajegheh ◽  
Peter Diamond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Cell Lines ◽  
Hind Limb ◽  
Clinical Manifestations ◽  
Disease Symptoms ◽  
Xenograft Mouse Model ◽  
Post Transplant ◽  
Human Multiple Myeloma ◽  
Hind Limb Paralysis

Abstract To facilitate human multiple myeloma (MM) engraftment into NOD/SCID recipients, mice were depleted of CD122+ cells (NK and myeloid cells) by antibody-mediated ablation prior to transplantation with the MM cell lines (RPMI8226, RPMI8226-TGL or U226). The MM engraftment, skeletal MM distribution, osteolysis, lambda chain paraprotein and associating disease symptoms in CD122+ cell-depleted and CD122+ cellreplete mice were compared. The CD122+ cell-depleted mice engrafted at a significantly higher frequency with human CD38+, CD56+, PCA-1+ and CD138+ cells. In the CD122+ cell-depleted mice, bioluminescence MM signal involved the whole mouse compared to limited imaging signal in the CD122+ cell-replete mice. The majority 88%–100% of CD122+ cell-depleted mice developed MM engraftment throughout the appendicular and axial skeletons with osteolysis and rare subcutaneous plasmacytomas (11% of mice). Serum paraprotein appeared earlier at 4–5 weeks post-transplant in CD122+ cell-depleted mice and continued to increase during the 12–13 weeks of analysis. The majority, 92% of CD122+ cell-depleted mice developed hind-limb paralysis and had a significantly shortened 45 day survival. Thus, depletion of CD122+ cells reduced resistance to the human MM and produced a new MM xenograft-NOD/SCID model that recapitulates the clinical manifestations of MM and eliminates the major limitations associated with the published MM xenograft-mouse model.

Tumor-associated macrophages modulate angiogenesis and tumor growth in a xenograft mouse model of multiple myeloma

2021 ◽  
Vol 110 ◽  
pp. 106709
Author(s):  
Miaomiao Sun ◽  
Qiankun Xiao ◽  
Xiaoqian Wang ◽  
Chenbo Yang ◽  
Chao Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Tumor Growth ◽  
Tumor Associated Macrophages ◽  
Xenograft Mouse Model
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