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)

Colorectal cancer (CRC) remains one of the most common gastrointestinal tumors, characterized by a poor survival rate. Effects of single use of homoharringtonine (HHT), approved for the treatment of acute myelocytic leukemia (AML) and chronic myeloid leukemia (CML), on CRC, are unknown. According to the TCGA database, EphB4 is aberrantly overexpressed in CRC patients. Therefore, the purpose of this study was to investigate the inhibitory effect of HHT on CRC and its underlying mechanism. HHT significantly suppressed LoVo cell growth in vitro and in vivo, and induced apoptosis and cell cycle arrest at the S phase. Mechanistic investigation using western blotting revealed that HHT suppressed EphB4, and this suppression was augmented by both HHT and NVP-BHG712 co-administration and EphB4 overexpression, indicating that HHT targets EphB4 to suppress LoVo cell growth. HHT inhibited EphB4 downstream pathways such as PI3K/AKT and MAPK/EKR1/2, resulting in the regulation of cell cycle-related molecules (cyclinA2 and CDC2), and the molecules in the Bcl-2 mitochondrial apoptosis pathway including Bcl-2, Mcl-1, Bax, Bad, caspase-3, caspase-7, and caspase-9. HHT may therefore be a promising EphB4 inhibitor with great potential for CRC treatment.
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PMID:Homoharringtonine suppresses LoVo cell growth by inhibiting EphB4 and the PI3K/AKT and MAPK/EKR1/2 signaling pathways. 3172 78

Lung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells. However, the underlying mechanisms involved remain poorly understood. Here, we reported the novel finding that PRIS significantly suppressed lung cancer growth in conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs). We demonstrated that PRIS inhibited the cell viabilities, migrative and invaded abilities, and capillary structure formation of CRLCs. Furthermore, our results clarified that PRIS induced mitochondrial dysfunction through reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and caspase-4, and expression of endoplasmic reticulum (ER) stress-associated proteins. Inhibition of ER stress by 4-PBA (4-phenylbutyric acid, a specific ER stress inhibitor) or CHOP siRNA transfection ameliorated PRIS-induced loss of mitochondrial membrane potential and intrinsic apoptosis. The present study also provides mechanistic evidence that PRIS suppressed the EphB4/CDC42/N-WASP signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and consequently resulting in suppressed cell viability, migration, and angiogenesis in CRLCs. Taken together, by providing a mechanistic insight into the modulation of ER stress-induced cell death in CRLCs by PRIS, we suggest that PRIS has a strong potential of being a new antitumor therapeutic agent with applications in the fields of human lung adenocarcinoma.
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PMID:Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling. 3273 36