A common pathway for chemotherapy-induced apoptosis in human squamous cell carcinoma lines distinct from that of receptor-mediated cell death.
Regulation of apoptosis by extracellular molecules binding to cell death receptors has received much attention in recent years. Fas, a member of the tumor necrosis factor receptor superfamily, is a transmembrane protein whose extracellular domain binds its cognate ligand (FasL), which can induce apoptosis in sensitive cells. Fas ligation leads to activation of cell death proteases, thereby initiating a proteolytic cascade which results in cellular fragmentation and death. Apoptosis is also regulated by inhibitory signals which promote cell survival. The bcl2 family of proteins is composed of both inhibitors and activators of programmed cell death. The bcl2 protein itself inhibits many apoptotic stimuli while other members of the bcl2 family such as bak and bid promote cell death. Many types of cancer chemotherapy induce cellular stress leading to induction of apoptosis. Stress-activated protein kinases such as p38 have been shown to inactivate bcl2 through phosphorylation and induce cleavage of bid. Deficiency of proapoptotic bcl2 family members has been associated with drug-resistant phenotypes. We report that exposure of human squamous cell carcinoma lines to different chemotherapy drugs activates a caspase cascade which is distinct from that of receptor-mediated apoptosis. The variable sensitivity of each cancer cell line to different forms of chemotherapy was not due to differences in caspase or bcl2 family protein expression. Rather, the stress-activated protein kinase p38 was overexpressed by resistant SCC lines which correlated with reductions in proapoptotic bid and bak protein expression. These two proteins exhibit distinct patterns of intracellular localization during chemotherapy-induced apoptosis.
Crowe
David L
DL
Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, USA. dcrowe@usc.edu
Yoon
Eiline
E
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C096429:L 709049; D020169:Caspases; D002945:Cisplatin