Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin (CDDP) is among the most widely used and most effective chemotherapeutic agent for many types of human cancer. Because killing cancer cells by chemotherapy is principally executed by apoptosis, a defective apoptotic program might acquire drug resistance. Flow cytometric Annexin V assay demonstrated that HEp-2 cells (human laryngeal cancer) were persistently resistant to CDDP as compared to HeLa cells (human uterine cervical cancer), despite the same histological type and wild-type p53 status. CDDP treatment caused steady induction of p53 protein in both cancer cell types, although it was more dramatic in CDDP-resistant HEp-2 cells, which was correlated well with p53 Ser15 phosphorylation, but not with the expression level of HPV type 18 E6 oncoprotein in these cells. Importantly, CDDP differently activated caspase cascades between HEp-2 and HeLa cells. CDDP activated the caspase-8 pathway through TNFR superfamily receptors such as Fas, but not caspase-9 in HeLa cells. On the other hand, the caspase-9 pathway was significantly activated in HEp-2 cells, although the activation of caspase-8 by CDDP was deficient. This different response to CDDP in caspase-8 activation was not related with the expression level of either Fas or FasL in these cells. We concluded from these results that loss of the caspase-8 activation pathway in HEp-2 cells was a possible mechanism for its resistance to CDDP-induced apoptosis. The caspase-8 pathway might play an important role in CDDP-induced apoptosis in HPV-positive human squamous cell carcinomas.
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PMID:Loss of caspase-8 activation pathway is a possible mechanism for CDDP resistance in human laryngeal squamous cell carcinoma, HEp-2 cells. 1528 75

Head and neck cancer is the sixth most common cancer worldwide and laryngeal cancer represents the largest subgroup. However, the molecular mechanism underlying its malignant behavior and progression is not clarified. Accumulating evidence has shown that Notch1 signaling pathway plays a central role in carcinogenesis, but its potential role in regulating the development of laryngeal carcinoma, has not been characterized. Here, we identified that Notch1 signaling pathway was activated in laryngeal carcinoma accompanied with up-regulation of Notch1 and Hes1 expression. Overexpression of Notch1 in laryngeal carcinoma cell line Hep-2 led to suppression of tumor cellular proliferation and arrested cell cycle in the G0/G1 phase and induced cell apoptosis, which were coupled with the down-regulation of cyclin D1, cyclin E, cdk2 and bcl-2 and up-regulation of caspase-3, caspase-9 and p53. Most importantly, up-regulation of Notch1 expression also reduced the migration of Hep-2 cells, which was closely associated with down-regulation of MMP-2 and MMP-9. The finding may lay a foundation for further investigations into the Notch1 signaling pathway as a potential target for laryngeal carcinoma.
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PMID:Potential role of Notch1 signaling pathway in laryngeal squamous cell carcinoma cell line Hep-2 involving proliferation inhibition, cell cycle arrest, cell apoptosis, and cell migration. 1972 60

Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to have anti-tumor effects, while the epidermal growth factor receptor (EGFR) signal pathway has been reported to play a vital role in the biological progression of several tumors and to be a target for therapeutic intervention. In this work, we show that inhibition of EGFR with tyrphostin AG1478 enhances oridonin-induced cell death in human laryngeal cancer cells HEp-2, a cell line characterized by EGFR gene amplification. The enhanced apoptotic effect correlates with high expression and activation of Bax, FADD, caspase-8 as well as caspase-3 and decreased protein levels of Bcl(2) and SIRT1, suggesting that both the extrinsic and intrinsic apoptosis pathways are involved in the apoptotic processes. However, treatment with oridonin and AG1478 greatly enhances nuclear translocation of apoptosis inducing factor (AIF) without caspase-9 activation, indicating that the apoptosis occurs via a caspase-9-independent mitochondrial pathway. Here, it is the active form of caspase-8 but not caspase-9 that activates downstream effector caspase-3, resulting in the cleavage of critical cellular proteins and apoptosis. Furthermore, the combined use of AG1478 and oridonin augments the production of reactive oxygen species (ROS). Incubation of cells with N-Acetylcysteine (NAC) attenuates the apoptosis and the mitochondrial membrane potential (Deltapsim) disruption induced by the combination of oridonin and AG1478, which indicates that ROS plays a pivotal role in cell death. In conclusion, targeting EGFR combined with other conventional pro-apoptotic drugs should be a potentially very effective anti-neoplastic therapy for laryngeal cancer.
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PMID:Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathways. 2020 41

Rabdosia rubescens, a commonly used traditional Chinese medicine, has increasingly gained attention for its use as an antitumor herb. Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to induce apoptosis in human laryngeal cancer HEp-2 cells by our group. Here, we made unexpected observations that the caspase-9 inhibitor (C9i) enhanced apoptosis in response to selected stimuli, and HEp-2 cells which were made deficient in caspase-9 using siRNA exhibited no resistance to apoptotic signals and actually demonstrated increased apoptotic sensitivity to oridonin. The results were reversed by the transfection of an exogenous caspase-9 expression vector. Caspase-9 reduced sensitivity to apoptotic stimuli through reactive oxygen species (ROS)-suppressing and autophagy-promoting methods. ROS triggered the progression of apoptosis through activation of both the caspase-9-independent mitochondrial pathway and death receptor pathways, and the autophagy had an anti-apoptotic function in oridonin-treated HEp-2 cells. These collective results suggest that oridonin targets caspase-9 to alter ROS production and autophagy situation to promote HEp-2 cell apoptosis. Therefore, oridonin has the potential to be developed as an anticancer agent, and the combination of oridonin with those agents leading to reduction of caspase-9 expression in tumor cells could represent a novel approach to human laryngeal cancer treatment.
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PMID:Inhibition of caspase-9 by oridonin, a diterpenoid isolated from Rabdosia rubescens, augments apoptosis in human laryngeal cancer cells. 2664 89

Long non-coding RNA (LncRNA) MEG3 serves a regulatory role in the progression of several types of cancer, but the role of MEG3 in laryngeal cancer is still unknown. The aim of this study was to explore the regulatory role and mechanism of MEG3 in laryngeal cancer. MEG3 expression in 50 laryngeal cancer tissue samples was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of MEG3 overexpression on laryngeal cancer cells were investigated in vitro and in vivo. The mechanism of competitive endogenous RNA (ceRNA) was validated through luciferase reporter assay, RT-qPCR and Western blotting. MEG3 was down-regulated in laryngeal cancer tissues, and the low MEG3 expression was associated with advanced clinical stage. Additionally, MEG3 overexpression inhibited the proliferation and induced the apoptosis of laryngeal cancer cells in vitro and in vivo. Particularly, MEG3 bound to miR-23a specifically and a reciprocal negative regulation existed between miR-23a and MEG3. Moreover, MEG3 up-regulated apoptotic protease activating factor-1 (APAF-1), a known miR-23a's target, thereby leading to the activation of caspase-9 and caspase-3. Meanwhile, these activated effects were rescued by miR-23a overexpression. In conclusion, the present study demonstrated that MEG3 functions as a novel tumour suppressive LncRNA in laryngeal cancer for the first time. Furthermore, MEG3 may act as a ceRNA to regulate APAF-1 expression by competitive binding to miR-23a, thereby regulating the progression of laryngeal cancer.
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PMID:LncRNA MEG3 inhibits cell proliferation and induces apoptosis in laryngeal cancer via miR-23a/APAF-1 axis. 3132 88