NF-Kappa B Modulation Is Involved in Celastrol Induced Human Multiple Myeloma Cell Apoptosis

Ni, Hong-Bo; Zhao, Wanzhou; Kong, Xiangtu; Li, Haitao; Ouyang, Jian

doi:10.1371/journal.pone.0095846

Cited by 45 publications

(34 citation statements)

References 47 publications

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“…In particular, they suggest that celastrol may inhibit the classical NF-κB pathway by preventing IκBα degradation, blocking p65 translocation and suppressing MMP-9 expression downstream of NF-κB. These results are consistent with those of previous studies (18,19,27), although other studies have suggested different mechanisms for the effects of celastrol on invasiveness (22,(35)(36)(37)(38). It should be noted that alternative mechanisms to the NF-κB pathway are also likely to contribute to the effects of celastrol on migration and invasion in the current models.…”

Section: Discussionsupporting

confidence: 91%

“…Celastrol strongly blocks the NF-κB pathway. To elucidate the molecular mechanisms by which celastrol affects ovarian cancer cells, proteins in the NF-κB pathway were analyzed, since this pathway is indicated to be one of the predominant mechanisms underlying the antitumor efficacy of celastrol (27). As shown in Fig.…”

Section: Anti-proliferative Effect Of Celastrol On Ovarian Cancer Cellsmentioning

confidence: 99%

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Celastrol inhibits migration and invasion through blocking the NF-κB pathway in ovarian cancer cells

Wang¹,

Zhai²,

Du³

2017

Experimental and Therapeutic Medicine

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Abstract. Metastatic ovarian cancer is a major clinical challenge with poor prognosis and high mortality. Celastrol is a natural compound that has exhibits antiproliferative activity; however, its effects on metastasis-related phenotypes in ovarian cancer models are unclear. In the current study, the anti-invasive activities and associated signaling pathways of celastrol were determined in ovarian cancer cells. Cell proliferation was tested by MTT assay. Cell migration was detected by wound healing and Transwell assays, while cell invasion was detected by a Matrigel-coated Transwell method. In addition, nuclear factor (NF)-κB and matrix metalloproteinase (MMP) expression was examined by western blotting, and MMP-2/-9 activities were determined by gelatin zymography. At sub-toxic concentrations (<0.5 µM), celastrol inhibited migration and invasion in a concentration-dependent manner in SKOV-3 and OVCAR-3 cells. At the molecular level, celastrol blocked the canonical NF-κB pathway by inhibiting IκBα phosphorylation, and preventing IκBα degradation and p65 accumulation. Furthermore, the expression and activity of the NF-κB target protein MMP-9, but not MMP-2, were inhibited by celastrol. Furthermore, celastrol showed no synergistic effect with MG132, an NF-κB inhibitor. In conclusion, celastrol exhibited significant anti-invasive activities in ovarian cancer cells. Such functions may be mediated via NF-κB pathway blockade. The results of this in vitro study strengthen the value of applying celastrol as a potential clinical intervention modality for delaying ovarian cancer metastasis. This, celastrol warrants further preclinical investigation.

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Section: Discussionsupporting

confidence: 91%

Section: Anti-proliferative Effect Of Celastrol On Ovarian Cancer Cellsmentioning

confidence: 99%

Celastrol inhibits migration and invasion through blocking the NF-κB pathway in ovarian cancer cells

Wang¹,

Zhai²,

Du³

2017

Experimental and Therapeutic Medicine

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“…MM is a clonal plasma cell malignancy with a clinical median overall survival of approximately 3–5 years. Most patients eventually experience relapse and chemoresistance, and ultimately die . The current challenge in MM studies is to pinpoint the critical factors that regulate growth and survival, so that potential therapeutic targets can be defined .…”

Section: Discussionmentioning

confidence: 99%

“…*P < 0.05 versus untreated U266 and RPMI8226 cells, **P < 0.01 versus untreated U266 cells, %P < 0.05 versus RPMI8226 cells treated with IL-6 alone, %%P < 0.01 versus U266 and RPMI8226 cells treated with IL-6 alone, # P < 0.05, ## P < 0.01. Most patients eventually experience relapse and chemoresistance, and ultimately die [30]. The current challenge in MM studies is to pinpoint the critical fac-tors that regulate growth and survival, so that potential therapeutic targets can be defined [7].…”

Section: Inhibiting the Expression Of Il-6 Induced By Ho-1 Sensitizedmentioning

confidence: 99%

Potential crosstalk of the interleukin‐6–heme oxygenase‐1‐dependent mechanism involved in resistance to lenalidomide in multiple myeloma cells

Wang

et al. 2016

The FEBS Journal

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Interleukin (IL)‐6 is one of the most important survival factors in multiple myeloma (MM), and determines the poor prognosis of MM. IL‐6 mainly has a paracrine bone marrow stromal cell origin and an autocrine MM cell origin. As an enzyme having cytoprotective effects, heme oxygenase‐1 (HO‐1) promotes the growth and drug resistance of various malignant tumors. HO‐1 expression levels in bone marrow CD138+ cells of MM patients were significantly higher than those in healthy donors, and positively correlated with both serum IL‐6 and intracellular IL‐6 mRNA expression levels. Culture of U266, RPMI8226 and CD138+ cells with exogenous IL‐6 in vitro induced high HO‐1 expression levels and allowed them to resist lenalidomide. It is hypothesized that this was probably attributable to IL‐6‐mediated activation of the Janus kinase 2–signal transducer and activator of transcription 3 pathway. In contrast, without IL‐6 coculture, enhanced HO‐1 expression in U266, RPMI8226 and bone marrow CD138+ cells from MM patients significantly inreased IL‐6 mRNA expression levels and facilitated autocrine IL‐6 production. The findings were associated with high HO‐1 expression‐enhanced p38 mitogen‐activated protein kinase phosphorylation. Reduced HO‐1 expression sensitized MM cells to lenalidomide. Therefore, we postulated that IL‐6 in the bone marrow microenvironment of MM patients stimulated high HO‐1 expression in MM cells and their resistance to lenalidomide. High HO‐1 expression also stimulated autocrine IL‐6 production, and exacerbated drug resistance and disease. This study supports the use of HO‐1 as a possible marker for both MM prognosis and drug resistance, and as a potential therapeutic target.

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“…Celastrol, a quinone methide triterpenoid, is isolated from the root of Tripterygium wilfordii and is primarily used for the treatment of autoimmune diseases and neurodegenerative diseases (3,4). In recent years, celastrol has exhibited great potential in inducing apoptosis of tumor cells and has shown significant progress for osteosarcoma treatment (5)(6)(7)(8)(9)(10). Apoptosis, known as type I-programmed cell death, mainly involves changes in cell morphology (e.g., chromosome condensation or fragmentation), shrinkage or invagination of the cell membrane and apoptotic bodies (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Effect and mechanisms of celastrol on the apoptosis of HOS osteosarcoma cells

Chen

Tao

et al. 2018

Oncol Rep

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Osteosarcoma is the most common primary malignant tumor of the bone found predominantly in children and teenagers and results in early metastasis and poor prognosis. The present study primarily focused on the impact of celastrol on apoptosis and autophagy of osteosarcoma HOS cells, as well as the related mechanisms. Following the appropriate treatment, the human osteosarcoma cell line HOS was assessed for viability, Ca2+ in cells, apoptosis and changes in cell morphology using Cell Counting Kit-8, flow cytometry, inverted phase contrast microscope, Hoechst staining and transmission electron microscopy. The expression levels of various proteins, including endoplasmic reticulum stress (ERS)-related proteins (Bip, PERK, p-PERK, IRE1α, calnexin, PDI and Erol‑Lα), apoptosis-related proteins (CHOP, cleaved caspase‑12), mitochondrial apoptosis-related proteins (Bax, Bcl-2 and cytochrome c), cleaved caspase-3, and autophagy-related proteins (LC3-Ⅰ, LC3-Ⅱ and P62) and β-actin, were assessed with western blotting. Celastrol significantly inhibited the viability of HOS cells in a dose-dependent manner and promoted the expression of ERS-related, apoptosis-related and mitochondrial apoptosis-related proteins. The ERS inhibitor tauroursodeoxycholate promoted celastrol-induced autophagy and apoptosis of HOS cells. Pretreatment with the PERK inhibitor GSK2656157 significantly promoted celastrol-induced death and attenuated HOS cell autophagy. Our results indicated that the ERS pathway and the mitochondrial pathway were involved in celastrol-induced apoptosis of HOS cells. The ERS/PERK pathway may protect HOS cells from apoptosis by celastrol and may play a complicated role in the process of autophagy.

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NF-Kappa B Modulation Is Involved in Celastrol Induced Human Multiple Myeloma Cell Apoptosis

Cited by 45 publications

References 47 publications

Celastrol inhibits migration and invasion through blocking the NF-κB pathway in ovarian cancer cells

Celastrol inhibits migration and invasion through blocking the NF-κB pathway in ovarian cancer cells

Potential crosstalk of the interleukin‐6–heme oxygenase‐1‐dependent mechanism involved in resistance to lenalidomide in multiple myeloma cells

Effect and mechanisms of celastrol on the apoptosis of HOS osteosarcoma cells

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