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)

Aberrant DNA hypermethylation is critical in the regulation of renewal and maintenance of cancer stem cells (CSCs), which represent targets for carcinogenic initiation by chemical and environmental agents. The administration of decitabine (DAC), which is a DNA hypermethylation inhibitor, is an attractive approach to enhancing the chemotherapeutic response and overcoming drug resistance by CSCs. In this study, we investigated whether low-dose DAC encapsulated in nanoparticles could be used to sensitize bulk breast cancer cells and CSCs to chemotherapy. In vitro studies revealed that treatment with nanoparticles loaded with low-dose DAC (NPDAC) combined with nanoparticles loaded with doxorubicin (NPDOX) better reduced the proportion of CSCs with high aldehyde dehydrogenase activity (ALDH(hi)) in the mammospheres of MDA-MB-231 cells, and better overcame the drug resistance by ALDH(hi) cells. Subsequently, systemic delivery of NPDAC significantly down-regulated the expression of DNMT1 and DNMT3b in a MB-MDA-231 xenograft murine model and induced increased caspase-9 expression, which contributed to the increased sensitivity of the bulk cancer cells and CSCs to NPDOX treatment. Importantly, the combined treatment of NPDAC and NPDOX resulted in the lowest proportion of ALDH(hi) CSCs and the highest proportion of apoptotic tumor cells, and the best tumor suppressive effects in inhibiting breast cancer growth.
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PMID:Combination therapy with epigenetic-targeted and chemotherapeutic drugs delivered by nanoparticles to enhance the chemotherapy response and overcome resistance by breast cancer stem cells. 2544 94

All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, has been extensively studied for the prevention and treatment of cancer; however, the underlying mechanism of its anti-cancer potential is still unclear. Here we found that ATRA induces apoptosis in p53-positive HepG2 cells, but not in p53-negative Hep3B cells. For this effect, ATRA activated p14 expression via promoter hypomethylation, resulting in ubiquitin-dependent degradation of mouse double minute 2 (MDM2) and subsequent stabilization of p53. The potential of ATRA to stabilize p53 was almost completely abolished by knock-down of p14 in HepG2 cells and was not observed in p14-negative A549 cells. Upregulation of p14 also abolished the self-regulatory potential of p53 to repress p14 expression via DNA methylation and transcriptionally activate MDM2 expression. The accumulated p53 then activated several apoptosis-related molecules, including Bax, PUMA, caspase-9, Bid, caspase-8, caspase-3, and PARP. Ectopic expression of DNA methyltransferase 1 almost completely abolished the potential of ATRA to activate the p14-MDM2-p53 pathway and induce p53-dependent apoptosis. Therefore, we conclude that ATRA induces p14 promoter hypomethylation to trigger apoptosis.
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PMID:All-trans retinoic acid induces p53-depenent apoptosis in human hepatocytes by activating p14 expression via promoter hypomethylation. 2582 71

The methylation inhibitor decitabine (DAC) has great therapeutic value for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, DAC monotherapy is associated with relatively low rates of overall response and complete remission. Previous studies have shown promising results for combination treatment regimens including DAC. Homoharringtonine (HHT), an alkaloid from Chinese natural plants and Cephalotaxus, has demonstrated potential for leukemia treatment. Our studies have suggested that the combination of DAC and HHT has synergistic effects for inhibiting the viability of SKM-1 and Kg-1a cells. This combination leads to enhanced inhibition of colony formation and apoptosis induction compared with DAC alone in SKM-1 but not Kg-1a cells. Only high-dose DAC and HHT significantly up-regulate caspase-3 and caspase-9 and inhibit BCL-XL in the SKM-1 cell line. The combined effects of DAC plus HHT on apoptosis may not only depend on regulation of the apoptosis-related genes we examined but others as well. HHT had no demethylation effects, and HHT in combination with DAC had no enhanced effects on hypomethylation and DNMT1, DNMT3A and DNMT3B mRNA expression in SKM-1 cells. Overall, these results suggest that DAC used in combination with HHT may have clinical potential for MDS treatment.
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PMID:Effects of the combination of decitabine and homoharringtonine in SKM-1 and Kg-1a cells. 2699 10

All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to activate p14 expression via promoter hypermethylation to induce p53-dependent apoptosis in human hepatocytes. In this study, we found that the oncogenic hepatitis B virus (HBV) X protein (HBx) of HBV, derived from both overexpression and 1.2-mer replicon systems, suppresses ATRA-induced apoptosis in p53-positive human hepatocytes. For this effect, HBx upregulated both protein and enzyme activity levels of DNA methyltransferase 1, 3a and 3b, in the presence of ATRA and thereby inhibited p14 expression via promoter hypermethylation, resulting in inactivation of the p14-mouse double minute 2 pathway and subsequent downregulation of p53 levels. As a result, HBx was able to impair the potential of ATRA to activate apoptosis-related molecules, including Bax, p53-upregulated modulator of apoptosis, caspase-9, caspase-3 and poly (ADP-ribose) polymerase. In conclusion, the present study provides a new oncogenic action mechanism of HBx, namely by suppressing the anticancer potential of ATRA to induce p53-dependent apoptosis in HBV-infected hepatocytes.
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PMID:Hepatitis B virus X protein suppresses all-trans retinoic acid-induced apoptosis in human hepatocytes by repressing p14 expression via DNA methylation. 2906 87

All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to induce p14 expression via promoter hypomethylation to activate the p14-MDM2-p53 pathway, which leads to activation of the p53-dependent apoptotic pathway and subsequent induction of apoptosis in human hepatoma cells. In the present study, we found that hepatitis C virus (HCV) Core derived from ectopic expression or HCV infection overcomes ATRA-induced apoptosis in p53-positive hepatoma cells. For this effect, HCV Core upregulated both protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b and thereby repressed p14 expression via promoter hypermethylation, resulting in inactivation of the pathway leading to p53 accumulation in the presence of ATRA. As a result, HCV Core prevented ATRA from activating several apoptosis-related molecules, including Bax, p53 upregulated modulator of apoptosis, caspase-9, caspase-3, and poly (ADP-ribose) polymerase. In addition, complementation of p14 in the Core-expressing cells by either ectopic expression or treatment with 5-Aza-2'dC almost completely abolished the potential of HCV Core to suppress ATRA-induced apoptosis. Based on these observations, we conclude that HCV Core executes its oncogenic potential by suppressing the p53-dependent apoptosis induced by ATRA in human hepatoma cells.
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PMID:Hepatitis C virus Core overcomes all-trans retinoic acid-induced apoptosis in human hepatoma cells by inhibiting p14 expression via DNA methylation. 2915 43

Apoptosis of granulosa cells (GCs) induced by hyperandrogen plays a key role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the mechanism of androgen-induced apoptosis of GCs has not been clarified to date. Recent studies have reported that PDCD4 expression is higher in PCOS patients and might be a key factor in PCOS progression. In this study, we aimed to investigate the role of PDCD4 in regulating apoptosis of human GCs and whether hyperandrogen regulate PDCD4 expression through DNA methylation. Overexpression of PDCD4 in human ovarian granulosa cell line KGN cells promoted cells apoptosis. Meanwhile, expression of caspase-3 and caspase-9 were significantly elevated. High concentration of testosterone treatment resulted in up-regulation of PDCD4 and a significant increase of apoptosis in KGN cells. In addition, knockdown of PDCD4 in KGN cells treated with high concentration of testosterone abolished the hyperandrogen-induced apoptosis. Furthermore, high concentration of testosterone down-regulated DNMT1, DNMT3A and DNMT3B expression and the methylation level in the promoter region of PDCD4 was decreased. In conclusion, PDCD4 can promote apoptosis of human ovarian GCs. The mechanism of hyperandrogen-induced apoptosis may be mediated by PDCD4. Furthermore, the up-regulation of PDCD4 induced by hyperandrogen may through demethylation of its promoter regions.
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PMID:Hyperandrogen enhances apoptosis of human ovarian granulosa cells via up-regulation and demethylation of PDCD4. 3142 17