Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of Wnt signaling plays a central role in the formation of hepatoblastoma (HB), the most common pediatric liver cancer. Blocking this pathway with specific inhibitors is currently the target of various research endeavours. This study provides evidence that the naturally occurring flavonoid epigallocatechin-3-gallate (EGCG) is highly effective against HB growth through inhibition of Wnt signaling. We demonstrate that EGCG has a strong cytotoxic effect on HB cells in a time- and dose-dependent manner by impinging on cell viability, while leaving normal fibroblasts unaffected. Apoptotic features, including morphological changes, caspase 3 activity, and proteolytic cleavage of poly(ADP-ribose) polymerase, were frequently found in EGCG-treated HB cells, thereby suggesting involvement of the mitochondrial intrinsic apoptotic pathway. We furthermore show that EGCG effectively inhibits Wnt signaling, as evidenced by down-regulation of Wnt-responsive reporter gene activity and expression of the Wnt target genes MYC and CCND1. Interestingly, EGCG induced reexpression of the tumor suppressor gene SFRP1, which is transcriptionally silenced in HB cells and known to down-regulate Wnt signaling. Considering the lack of toxic effects on normal cells, EGCG should be preclinically validated as an adjuvant therapy in vivo with the ultimate goal of determining its efficacy in human trials.
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PMID:Epigallocatechin-3-gallate inhibits hepatoblastoma growth by reactivating the Wnt inhibitor SFRP1. 2412 55

Hepatoblastoma (HB) is the most type of common pediatric liver cancer. The primary chemotherapy drug for HB is cisplatin (DDP). However, patients readily develop intrinsic and acquired resistance, and severe side effects to treatment. Sphingomyelin synthase 2 (SMS2) is a key enzyme involved in the generation of sphingomyelin (SM), which is able to regulate cell proliferation, apoptosis and differentiation. The death receptors (DRs) have important functions in DDP-induced apoptosis. However, whether SMS2 is able to modulate cell apoptosis through the DR signaling pathway remains unknown. To investigate this question, SMS2 was overexpressed in HepG2 cells and treated with 3.5 mg/l cisplatin in the present study. After 24 h, the expression of SMS2, avian myelocytomatosis viral oncogene homolog (c-Myc), DR4, DR5 and caspase-3 was analyzed. Furthermore, cell viability was quantified, and apoptosis was assessed by western blot and flow cytometry analysis as well as Cell Counting kit-8. The results of the present study revealed that overexpression of SMS2 was able to increase the expression of c-Myc, cleaved caspase-3, DR4 and DR5 compared with the control group (P<0.05, n=3), and increase the levels of apoptosis in the SMS2 + DDP group, compared with the control (P<0.001, n=3). These results indicate that overexpression of SMS2 is able to improve sensitivity of HepG2 cells to DDP by increasing the expression of c-Myc, DR4 and DR5 in HepG2 cells. This increased sensitivity may decrease intrinsic and acquired resistance of chemotherapy in HB, and reduce the associated severe side effects in pediatric patients.
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PMID:Sphingomyelin synthase 2 overexpression promotes cisplatin-induced apoptosis of HepG2 cells. 2937 16