Knockdown of REGγ inhibits the proliferation and migration and promotes the apoptosis of multiple myeloma cells by downregulating NF-κB signal pathway

Liu, Shuang; Zheng, Li; Zhu, Yongjian; Shen, Huijuan; Zhong, Qi; Huang, Jing; Cheng, Li; Zhi, Liu; Yao, Mengdong; Ou, Ruiming; Zhang, Qing

doi:10.1080/10245332.2017.1385194

Cited by 11 publications

(12 citation statements)

References 28 publications

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“…The starting material, 2-chloro-1-methyl-1H-benzimidazole (1) as the starting material, was reacted with hydrazine hydrate to obtain intermediate 2, which was then reacted with 5-bromo-2-hydroxy-1,3 benzenedicarboxaldehyde (4). The reaction produced the target product (5). The NMR spectra of AE-848 are shown in Supplementary Figure 1.…”

Section: Results Chemistrymentioning

confidence: 99%

“…Hyperactivated NF-κB signaling thus serves as an important prognostic biomarker and therapeutic target for MM. 4,5 The PI3K/Akt/mTOR signaling pathway controls a number of biological processes critical to tumorigenesis, including apoptosis, transcription, translation, and cell cycle. 6 A growing number of studies have shown that inhibition of the PI3K/Akt/mTOR signaling pathway triggers apoptosis in MM cells.…”

Section: Introductionmentioning

confidence: 99%

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Novel Small Molecular Compound AE-848 Potently Induces Human Multiple Myeloma Cell Apoptosis by Modulating the NF-κB and PI3K/Akt/mTOR Signaling Pathways

Xu¹,

Feng²,

Zhou³

et al. 2020

OTT

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Background We aimed to investigate the anti-multiple myeloma (MM) activity of the new small molecular compound AE-848 (5-bromo-2-hydroxyisophthalaldehyde bis[(1-methyl-1H-benzimidazol-2-yl)hydrazone]) and its underlying anti-MM mechanism. Methods Cell viability and apoptosis were detected and quantified by using MTT and flow cytometry, respectively. JC-1 dye-related techniques were used to assess mitochondrial membrane potential (MMP). Western blotting was applied to detect the expression of NF-κB and PI3K/Akt/mTOR pathway-associated proteins. The in vivo activity of AE-848 against MM was evaluated in a MM mouse model. Results Application of AE-848 into the in vitro cell culture system significantly reduced the viability and induced apoptosis of the MM cell lines, RPMI-8226 and U266, in a dose- and time-dependent manner, respectively. JC-1 dye and Western blotting analysis revealed that AE-848 induced the cleavage of caspase-8, caspase-3, and poly ADP-ribose polymerase (PARP), resulting in loss of mitochondrial membrane potential (MMP). Both the NF-κB and PI3K/AKT/mTOR signaling pathways were involved in AE-848-induced apoptosis of U266 and RPMI8226 cells. Moreover, AE-848 leads to cell cycle arrest of MM cells. Its anti-MM efficacy was further confirmed in a xenograft model of MM. AE-848 administration significantly inhibited MM tumor progression and prolonged the survival of MM-bearing mice. More importantly, our results demonstrated that AE-848 markedly induced primary MM cell apoptosis. Conclusion Our results for the first time showed that the small compound AE-848 had potent in vitro and in vivo anti-myeloma activity, indicating that AE-848 may have great potential to be developed as a drug for MM treatment.

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Section: Results Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Small Molecular Compound AE-848 Potently Induces Human Multiple Myeloma Cell Apoptosis by Modulating the NF-κB and PI3K/Akt/mTOR Signaling Pathways

Xu¹,

Feng²,

Zhou³

et al. 2020

OTT

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“…Our data also demonstrated that PDTC treatment significantly inhibited the USP15-mediated expression of NF-κB-regulated gene products in MM cells. Inhibition of NF-κBp65 expression in MM cells significantly reduced proliferation and apoptosis and decreased Bcl-2 and Bcl-xL expression 28 , 29 . NF-κB inactivation decreases Bcl-2, Bcl-xL and Survivin expression and subsequently activates Caspase-3, which results in MM cell apoptosis 30 , 31 .…”

Section: Discussionmentioning

confidence: 96%

USP15 inhibits multiple myeloma cell apoptosis through activating a feedback loop with the transcription factor NF-κBp65

Zhou

Jiang

et al. 2018

Exp Mol Med

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USP15 has been shown to stabilize transcription factors, to be amplified in many cancers and to mediate cancer cell survival. However, the underlying mechanism by which USP15 regulates multiple myeloma (MM) cell proliferation and apoptosis has not been established. Here, our results showed that USP15 mRNA expression was upregulated in MM patients. USP15 silencing induced MM cell proliferation inhibition, apoptosis, and the expression of nuclear and cytoplasmic NF-κBp65, while USP15 overexpression exhibited an inverse effect. Moreover, in vivo experiments indicated that USP15 silencing inhibited MM tumor growth and NF-κBp65 expression. PDTC treatment significantly inhibited USP15 overexpression-induced cell proliferation, apoptosis inhibition, and NF-κBp65 expression. USP15 overexpression promoted NF-κBp65 expression through inhibition of its ubiquitination, whereas NF-κBp65 promoted USP15 expression as a positive regulator. Taken together, the USP15-NF-κBp65 loop is involved in MM tumorigenesis and may be a potential therapeutic target for MM.

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“…In the past decades, researchers have aimed at elucidating the mechanisms regulating the malignant behaviour of MM and identifying key genes contributing to cancer progression. A previous study revealed that knockdown of REGγ inhibits the proliferation and migration, but promotes the apoptosis of MM cells, suggesting that REGγ may serve as a therapeutic target for MM . Additionally, cullin 4A is considered as a marker and promising therapeutic target in MM.…”

Section: Discussionmentioning

confidence: 99%

Platycodin D inhibits proliferation, migration and induces chemosensitization through inactivation of the NF‐κB and JAK2/STAT3 pathways in multiple myeloma cells

Zhang

Chen

et al. 2019

Clin Exp Pharma Physio

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Multiple myeloma (MM) is a malignancy characterized by the proliferation of malignant plasma cells. Platycodin D (PLD) is a triterpenoid saponin that exerts anti‐tumour activity through multiple mechanisms. However, the role of PLD in MM remains unknown. Here, we investigated the effect of PLD on MM cell lines NCI‐H929 and U266B1, and elucidated the underlying molecular mechanism. Cell Counting Kit‐8 assay showed that the proliferation of NCI‐H929 and U266B1 cells was significantly decreased after PLD treatment. Transwell assay confirmed that PLD treatment suppressed migration of NCI‐H929 and U266B1 cells. Flow cytometry results indicated that the apoptotic rates of bortezomib (BTZ)‐treated NCI‐H929 and U266B1 cells were markedly increased after PLD treatment. Western blot analysis revealed that bcl‐2 expression was decreased, while bax expression was increased in PLD‐treated NCI‐H929 and U266B1 cells compared with that in BTZ‐treated cells. Furthermore, PLD treatment blocked the activation of nuclear factor‐kappa B (NF‐κB) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling pathways in NCI‐H929 cells. Taken together, these data showed that PLD inhibited proliferation and migration, and enhanced chemosensitization to BTZ through inactivation of the NF‐κB and JAK2/STAT3 pathways in MM cell lines. These findings indicated that PLD might serve as a novel therapeutic agent for the treatment of MM.

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Knockdown of REGγ inhibits the proliferation and migration and promotes the apoptosis of multiple myeloma cells by downregulating NF-κB signal pathway

Abstract: Knockdown of REGγ may inhibit the proliferation and migration, and promote the apoptosis of RPMI-8226 cells possibly by downregulating NF-κB signal pathway.

Cited by 11 publications

References 28 publications

Novel Small Molecular Compound AE-848 Potently Induces Human Multiple Myeloma Cell Apoptosis by Modulating the NF-κB and PI3K/Akt/mTOR Signaling Pathways

Novel Small Molecular Compound AE-848 Potently Induces Human Multiple Myeloma Cell Apoptosis by Modulating the NF-κB and PI3K/Akt/mTOR Signaling Pathways

USP15 inhibits multiple myeloma cell apoptosis through activating a feedback loop with the transcription factor NF-κBp65

Platycodin D inhibits proliferation, migration and induces chemosensitization through inactivation of the NF‐κB and JAK2/STAT3 pathways in multiple myeloma cells

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