Synthetic retinoid CD437 induces apoptosis of esophageal squamous HET-1A cells through the caspase-3-dependent pathway.
6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) is a novel retinoid that has shown to be a potent inducer of apoptosis in cancer cells. We investigated the apoptosis-inducing activity of CD437 and its mechanism of action in the human esophageal squamous epithelial cell line (HET-1A). CD437 decreased HET-1A cell viability in a time and dose dependent manner. CD437 was found to induce DNA fragmentation. Apoptosis was accompanied by markedly increased activity of caspase-3 as well expression of caspase-3 and -8 and APRP fragmentation. The CD437-mediated activation of caspase-3 was inhibited by Z-DEVD-FMK These data indicate that CD437-induced apoptosis in HET-1A cells may be mediated through the caspase-3 dependent pathway. In addition, apoptosis was also accompanied by increased expression of Bad protein and down-regulation of Bcl-2 expression. Phosphorylation of Jun occurred following CD437 exposure indicating that Jun kinase (JNK) activity was strongly induced by CD437. Understanding these apoptotic pathways of esophageal epithelial cells may allow therapeutic induction of cell death in malignant orpremalignant lesions of the esophagus by agents such as CD437.
Wan
X
X
Section of Surgical Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Duncan
M D
MD
Nass
P
P
Harmon
J W
JW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004947:Esophagus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D051025:bcl-Associated Death Protein
D000970:Antineoplastic Agents; C494819:BAD protein, human; C099555:CD 437; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012176:Retinoids; D051025:bcl-Associated Death Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases