Cyclin D1 Amplification in Multiple Myeloma Is Associated With Multidrug Resistance Expression

Sewify, Eman M.; Afifi, Ola; Mosad, Eman; Zaki, Amen H.; Gammal, Sahar A. El

doi:10.1016/j.clml.2013.07.008

Cited by 32 publications

(28 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The canonical WNT signaling can trigger the destabilization of the multi-protein destruction complex and the subsequent stabilization of b-catenin [61]. When cytoplasmic b-catenin is stabilized by WNT signaling, it forms a complex with accessory proteins, resulting in the transcription of important growth-promoting genes, such as c-MYC and Cyclin D1, both of which are frequently deregulated in MM [62,63].…”

Section: Wnt/b-cateninmentioning

confidence: 99%

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

Guo

McKenna

O’Dwyer

et al. 2015

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

Section: Wnt/b-cateninmentioning

confidence: 99%

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

Guo

McKenna

O’Dwyer

et al. 2015

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

“…17 However, bortezomib also increases constitutive NF-kb expression levels by activating IKKb, leading to NF-kb nuclear translocation and the transcription of multiple NFkb-regulated genes including Survivin, and Cyclin D1, which are associated with multi-drug resistance in MM. [18][19][20] This upregulation of NF-kb expression and its signaling pathway has been associated with acquisition of bortezomib resistance due to prolonged drug exposure in MM. 13,18 However, the role of the NF-kb signaling pathway in hypoxia-induced bortezomib resistance in MM is unknown.…”

Section: Introductionmentioning

confidence: 99%

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

et al. 2016

View full text Add to dashboard Cite

Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxicmyeloma cells to bortezomib. Hypoxia increased NF-kb subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-kb p65 protein levels in the nucleus and reduced the expression of NF-kb-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the na€ ıve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-kb-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-kb signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomibresistance and improve survival outcomes of MM patients.

show abstract

“…In numerous types of cancer, excessive cell cycle proteins allow for fast growth of tumor cells (42,43). It has been demonstrated that abnormal CCND1 is present in breast, lung, endometrial, pancreatic and testicular cancer, multiple myeloma and other types of blood cancer (44)(45)(46)(47)(48). Mutation, amplification and over-expression of CCND1 may alter the cell cycle process.…”

mentioning

confidence: 99%

Role of microRNA-4458 in patients with non-small-cell lung cancer

et al. 2016

View full text Add to dashboard Cite

Abstract. Incidence and progression of non-small-cell lung cancer (NSCLC) is a multi-factor, multi-step process. The present study investigated the association between the expression level of microRNA (miR)-4458 in NSCLC and paracarcinoma liver tissues and survival rates, and studied the biological functions of miR-4458 at the cellular and protein level. NSCLC and paracarcinoma tissues were sequenced using a miR expression chip. The association between miR-4458 expression and tumor-node-metastasis staging, total survival rate and relapse-free survival rate was analyzed. miR-4458 was subjected to target gene prediction. The target protein of cyclin D1 (CCND1) was verified with western blot analysis, immunohistochemistry and a luciferase reporter assay. The relative level of miR-4458 in paracarcinoma tissues of 9 NSCLC patients decreased from 2.38 to 0.65 (P<0.001). Total five-year survival rates of the high-expression miR-4458 group (29.21%) significantly exceeded that of the low-expression group (14.37%) (P=0.025). The viability of human lung carcinoma A549 and H460 cells transfected with miR-4458 decreased significantly compared with cells transfected with a normal control (blank control plasmid) within 72 h (P<0.001). The percentage of A549 and H460 cells transfected with a miR-4458 mimic at the cell cycle stage G0/G1 was 69.94±8.05 and 68.15±7.75%, respectively. The percentages increased significantly compared with the control group (46.06±6.93 for A549 cells; 45.22±7.24 for H640 cells; P<0.001). CCND1 mRNA was downregulated significantly in H460 cells 72 h subsequent to the addition of miR-4458 mimics (P<0.001). The activity of mutant-CCND1 altered slightly, while the fluorescence intensity of the wild-type-CCND1 group decreased significantly following the addition of miR-4458 mimics. In conclusion, miR-4458 was expressed at low levels in lung cancer tissues, and it arrested cells in vitro at stage G0/G1 and inhibited cell proliferation. Therefore, miR-4458 may participate in the onset of lung cancer as a suppressor gene by inhibiting CCND1.

show abstract

Cyclin D1 Amplification in Multiple Myeloma Is Associated With Multidrug Resistance Expression

Cited by 32 publications

References 16 publications

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

Role of microRNA-4458 in patients with non-small-cell lung cancer

Contact Info

Product

Resources

About