Cardiac glycoside induces cell death via FasL by activating calcineurin and NF-AT, but apoptosis initially proceeds through activation of caspases.
Decrease in caspase activity is a common phenomenon in drug resistance. For effective therapeutic intervention, detection of such agents, which affects other pathway independent of caspases to promote cell death, might be important. Oleandrin, a polyphenolic glycoside induced cell death through activation of caspases in a variety of human tumour cells. In this report we provide evidence that besides caspases activation, oleandrin interacts with plasma membrane, changes fluidity of the membrane, disrupts Na(+)/K(+)-ATPase pump, enhances intracellular free Ca(2+) and thereby activates calcineurin. Calcineurin, in turns, activates nuclear transcription factor NF-AT and its dependent genes such as FasL, which induces cell death as a late response of oleandrin. Cell death at early stages is mediated by caspases where inhibitors partially protected oleandrin-mediated cell death in vector-transfected cells, but almost completely in Bcl-xL-overexpressed cells. Overall, our data suggest that oleandrin might be important therapeutic molecule in case of tumors where cell death pathway occurs due to deregulation of caspase-mediated pathway.
Raghavendra
Pongali B
PB
Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nacharam, Hyderabad, 500076, India.
Sreenivasan
Yashin
Y
Ramesh
Govindarajan T
GT
Manna
Sunil K
SK
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D002298:Cardenolides / Q000494:pharmacology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000494:pharmacology; D008560:Membrane Fluidity / Q000187:drug effects; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009336:Necrosis; D009842:Oligopeptides; D021381:Protein Transport / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D065095:Calcineurin Inhibitors; D002298:Cardenolides; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D008055:Lipids; D050778:NFATC Transcription Factors; D009842:Oligopeptides; D051020:bcl-X Protein; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D003609:Dactinomycin; D016572:Cyclosporine; D004247:DNA; D019703:Calcineurin; D020169:Caspases; D000254:Sodium-Potassium-Exchanging ATPase; C021065:oleandrin; D002118:Calcium