Celastrol inhibits growth and induces apoptotic cell death in melanoma cells via the activation ROS-dependent mitochondrial pathway and the suppression of PI3K/AKT signaling

Lee, Ju Hye; Won, Yeong Seon; Park, Ki Hun; Lee, Mi Kyung; Tachibana, Hirofumi; Yamada, Koji; Seo, Kwon Il

doi:10.1007/s10495-012-0767-5

Cited by 115 publications

(75 citation statements)

References 55 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: 90%

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: 90%

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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“…The current study indicates that celastrol treatment reduced the protein expression levels of PI3K and p-Akt in OVCAR3 cells. In a previous study, Lee et al (29) indicated that treatment with celastrol was able to suppress cell growth and increase apoptosis in melanoma cells through the suppression of PI3K/AKT signaling. Sha et al (16) demonstrated that celastrol induces apoptosis in gastric cancer cells via the inhibition of the PI3K/Akt-NF-κB signaling pathway by miRNA-21.…”

Section: Discussionmentioning

confidence: 99%

Effects of celastrol on enhancing apoptosis of ovarian cancer cells via the downregulation of microRNA-21 and the suppression of the PI3K/Akt-NF-κB signaling pathway in an in vitro model of ovarian carcinoma

Zhang

et al. 2016

Molecular Medicine Reports

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Abstract. Celastrol has previously been used to treat rheumatoid arthritis, bruises, back pain and additional diseases. At present, efficacy studies predominantly focus on the anti-inflammatory, antioxidative and antitumor effects of celastrol. However, the effect of celastrol on ovarian cancer cells is not fully elucidated. In the present study, the effects of celastrol were investigated in ovarian cancer cells and the mechanisms involved were explored. In OVCAR3 cells, celastrol was observed to suppress cellular proliferation, induce apoptosis and increase caspase-9 and -3 activity in a dose-and time-dependent manner. The expression levels of microRNA-21 (miRNA-21) were reduced, in addition to a reduction in the levels of phosphoinositide 3-kinase (PI3K)/p-Akt-NF (NF)-κB following treatment with celastrol. Notably, reduced expression of miRNA-21 replicated the effect of celastrol on OVCAR3 cells and inhibited the PI3K/p-Akt-NF-κB signaling pathway in an in vitro model of ovarian carcinoma. To the best of our knowledge this is the first study to indicate that celastrol may represent a potential agent for the treatment of human ovarian carcinoma, via the induction of apoptosis through the downregulation of miRNA-21 and the PI3K/Akt-NF-κB signaling pathway in an in vitro model of ovarian carcinoma.

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“…High endogenous ROS concentrations in malignant cells may also render these cells more vulnerable to further stresses (34,39,40). Hence, anticancer therapies that trigger a further increase in ROS formation may induce cell death in cancer cells compared with their non-malignant counterparts (34,41,42). In addition, ROS can limit malignant growth by triggering activation of p53, whereas antioxidants enhanced tumor progression in a p53-dependent manner (17).…”

Section: Gr1mentioning

confidence: 99%

Role of NOX2-Derived Reactive Oxygen Species in NK Cell–Mediated Control of Murine Melanoma Metastasis

Aydin

Johansson

Nazir

et al. 2017

Cancer Immunology Research

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The NADPH oxidase of myeloid cells, NOX2, generates reactive oxygen species (ROS) to eliminate pathogens and malignant cells. NOX2-derived ROS have also been proposed to dampen functions of natural killer (NK) cells and other antineoplastic lymphocytes in the microenvironment of established tumors. The mechanisms by which NOX2 and ROS influence the process of distant metastasis have only been partially explored. Here, we utilized genetically NOX2-deficient mice and pharmacologic inhibition of NOX2 to elucidate the role of NOX2 for the hematogenous metastasis of melanoma cells. After intravenous inoculation of B16F1 or B16F10 cells, lung metastasis formation was reduced in B6.129S6-Cybb tm1DinK (Nox2-KO) versus Nox2-sufficient wild-type (WT) mice. Systemic treatment with the NOX2-inhibitor histamine dihydrochloride (HDC) reduced melanoma metastasis and enhanced the infiltration of IFNg-producing NK cells into lungs of WT but not of Nox2-KO mice. IFNg-deficient B6.129S7-Ifng tm1Ts /J mice were prone to develop melanoma metastases and did not respond to in vivo treatment with HDC. We propose that NOX2-derived ROS facilitate metastasis of melanoma cells by downmodulating NK-cell function and that inhibition of NOX2 may restore IFNg-dependent, NK cell-mediated clearance of melanoma cells. Cancer Immunol Res; 5(9); 804-11. Ó2017AACR.

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Celastrol inhibits growth and induces apoptotic cell death in melanoma cells via the activation ROS-dependent mitochondrial pathway and the suppression of PI3K/AKT signaling

Cited by 115 publications

References 55 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

Effects of celastrol on enhancing apoptosis of ovarian cancer cells via the downregulation of microRNA-21 and the suppression of the PI3K/Akt-NF-κB signaling pathway in an in vitro model of ovarian carcinoma

Role of NOX2-Derived Reactive Oxygen Species in NK Cell–Mediated Control of Murine Melanoma Metastasis

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