Inhibitory action of Celastrol on hypoxia-mediated angiogenesis and metastasis via the HIF-1α pathway

Huang, Lili; Zhang, Zefu; Zhang, Sheng; Ren, Jinghua; Zhang, Ruiguang; Zeng, Hui; Li, Qingfeng; Wu, Gang

doi:10.3892/ijmm.2011.600

Cited by 27 publications

(12 citation statements)

References 22 publications

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“…A previous study showed that treating HepG2 cells with Celastrol for 16 h decreased the HIF-1α mRNA level under normoxia and hypoxia and inhibited hypoxia-induced accumulation of the HIF-1α protein in the nuclei of HepG2 cells [15]; however, in our study, exposure of HepG2 cells for a shorter amount of time yielded the opposite result. In our system, treating cells with Celastrol for 6 h did not influence HIF-1α transcription, as its mRNA level did not change after Celastrol treatment under normoxia or hypoxia.…”

Section: Discussioncontrasting

confidence: 93%

“…In addition to treating autoimmune and neurodegenerative diseases by its anti-oxidative and anti-inflammatory effects [4], [5], Celastrol is frequently investigated for its potential anti-cancer activities in vitro and in vivo , including inhibiting tumor cell proliferation, inducing apoptosis in different types of cancer cells [6]–[9] and synergistically enhancing the cytotoxicity of radiotherapy and some chemotherapeutic agents [10]–[13]. Although previous studies have reported that Celastrol has the potential to inhibit HIF-1α mRNA transcription and suppress hypoxia-induced angiogenesis and tumor metastasis [14], [15], in this study, we found that a short amount of time exposure of Celastrol did not affect the HIF-1α mRNA levels. Instead, we found that Celastrol could induce HIF-1α protein accumulation in multiple cancer cell lines in an oxygen-independent manner and that the enhanced HIF-1α protein entered the nucleus and promoted the transcription of the HIF-1 target genes VEGF and Glut-1.…”

Section: Introductionmentioning

confidence: 99%

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Celastrol Stimulates Hypoxia-Inducible Factor-1 Activity in Tumor Cells by Initiating the ROS/Akt/p70S6K Signaling Pathway and Enhancing Hypoxia-Inducible Factor-1α Protein Synthesis

Han

Sun

Zhao³

et al. 2014

PLoS ONE

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Celastrol, a tripterine derived from the traditional Chinese medicine plant Tripterygium wilfordii Hook F. (“Thunder of God Vine”), has been reported to have multiple effects, such as anti-inflammation, suppression of tumor angiogenesis, inhibition of tumor growth, induction of apoptosis and protection of cells against human neurodegenerative diseases. However, the mechanisms that underlie these functions are not well defined. In this study, we reported for the first time that Celastrol could induce HIF-1α protein accumulation in multiple cancer cell lines in an oxygen-independent manner and that the enhanced HIF-1α protein entered the nucleus and promoted the transcription of the HIF-1 target genes VEGF and Glut-1. Celastrol did not influence HIF-1α transcription. Instead, Celastrol induced the accumulation of the HIF-1α protein by inducing ROS and activating Akt/p70S6K signaling to promote HIF-1α translation. In addition, we found that the activation of Akt by Celastrol was transient. With increased exposure time, inhibition of Hsp90 chaperone function by Celastrol led to the subsequent depletion of the Akt protein and thus to the suppression of Akt activity. Moreover, in HepG2 cells, the accumulation of HIF-1α increased the expression of BNIP3, which induced autophagy. However, HIF-1α and BNIP3 did not influence the cytotoxicity of Celastrol because the main mechanism by which Celastrol kills cancer cells is through stimulating ROS-mediated JNK activation and inducing apoptosis. Furthermore, our data showed that the dose required for Celastrol to induce HIF-1α protein accumulation and enhance HIF-1α transcriptional activation was below its cytotoxic threshold. A cytotoxic dose of Celastrol for cancer cells did not display cytotoxicity in LO2 normal human liver cells, which indicated that the novel functions of Celastrol in regulating HIF-1 signaling and inducing autophagy might be used in new applications, such as in anti-inflammation and protection of cells against human neurodegenerative diseases. Future studies regarding these applications are required.

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Section: Discussioncontrasting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Celastrol Stimulates Hypoxia-Inducible Factor-1 Activity in Tumor Cells by Initiating the ROS/Akt/p70S6K Signaling Pathway and Enhancing Hypoxia-Inducible Factor-1α Protein Synthesis

Han

Sun

Zhao³

et al. 2014

PLoS ONE

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“…The inhibitory effect of celastrol on angiogenesis is mediated by the suppression of HIF-1α, through HSP90 (122) and mTOR/p70S6K/eIF4E pathway inhibition and ERK1/2 phosphorylation (123, 124). This inhibition of HIF-1α leads to the decrease of its target genes, such as the VEGF , that are crucial in the angiogenic process.…”

Section: Anticancer Properties Of Celastrolmentioning

confidence: 99%

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases

2017

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The identification of new bioactive compounds derived from medicinal plants with significant therapeutic properties has attracted considerable interest in recent years. Such is the case of the Tripterygium wilfordii (TW), an herb used in Chinese medicine. Clinical trials performed so far using its root extracts have shown impressive therapeutic properties but also revealed substantial gastrointestinal side effects. The most promising bioactive compound obtained from TW is celastrol. During the last decade, an increasing number of studies were published highlighting the medicinal usefulness of celastrol in diverse clinical areas. Here we systematically review the mechanism of action and the therapeutic properties of celastrol in inflammatory diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, osteoarthritis and allergy, as well as in cancer, neurodegenerative disorders and other diseases, such as diabetes, obesity, atherosclerosis, and hearing loss. We will also focus in the toxicological profile and limitations of celastrol formulation, namely, solubility, bioavailability, and dosage issues that still limit its further clinical application and usefulness.

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“…HIF-1β is considered to be an aryl hydrocarbon nuclear translocator (ARNT), whereas HIF-1α has been recognized as an oxygen-regulated subunit that mediates the function of HIF-1 (3). A series of studies have previously shown that the overexpression of HIF-1α was involved in the pathogenesis of tumor angiogenesis (4,5), invasion (6,7), metastasis (6–8) and resistance to chemotherapy (9,10). Several studies have focused on whether HIF-1α expression in human laryngeal carcinoma tissue is associated with tumor progression and lymph node metastasis.…”

Section: Introductionmentioning

confidence: 99%

Expression and significance of hypoxia-inducible factor-1α and MDR1/P-glycoprotein in laryngeal carcinoma tissue and hypoxic Hep-2 cells

Xie

Chen

et al. 2013

Oncology Letters

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The present study aimed to evaluate the expression of hypoxia-inducible factor-1α (HIF-1α) and MDR1/P-glycoprotein (P-gp) in human laryngeal squamous cell carcinoma (LSCC) tissues, and also to investigate the regulation of MDR1 gene expression by HIF-1α in Hep-2 cells under hypoxic conditions. The expression of HIF-1α and MDR1/P-gp in human LSCC tissues was examined using immunohistochemistry. The HIF-1α and MDR1 gene expression in the Hep-2 cells was detected using real-time quantitative reverse transcription (QRT)-PCR and western blot analysis under normoxic and hypoxic conditions. In hypoxia, HIF-1α expression was inhibited by RNA interference. HIF-1α and MDR1/P-gp expression was high in the LSCC tissues and was associated with the clinical stage and lymph node metastasis (P<0.05). HIF-1α expression was positively correlated with MDR1/P-gp expression (P<0.01). In the Hep-2 cells, HIF-1α and MDR1/P-gp expression significantly increased in response to hypoxia. The inhibition of HIF-1α expression synergistically downregulated the expression of the MDR1 gene in hypoxic Hep-2 cells. HIF-1α expression is positively correlated with MDR1/P-gp expression in LSCC, and the two proteins may be able to serve as potential biomarkers for predicting the malignant progression and metastasis of LSCC. HIF-1α may be critical for the upregulation of MDR1 gene expression induced by hypoxia in Hep-2 cells.

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Inhibitory action of Celastrol on hypoxia-mediated angiogenesis and metastasis via the HIF-1α pathway

Cited by 27 publications

References 22 publications

Celastrol Stimulates Hypoxia-Inducible Factor-1 Activity in Tumor Cells by Initiating the ROS/Akt/p70S6K Signaling Pathway and Enhancing Hypoxia-Inducible Factor-1α Protein Synthesis

Celastrol Stimulates Hypoxia-Inducible Factor-1 Activity in Tumor Cells by Initiating the ROS/Akt/p70S6K Signaling Pathway and Enhancing Hypoxia-Inducible Factor-1α Protein Synthesis

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases

Expression and significance of hypoxia-inducible factor-1α and MDR1/P-glycoprotein in laryngeal carcinoma tissue and hypoxic Hep-2 cells

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