Role of STAT3 and NFkappaB signaling in the serum factor-induced apoptosis in AK-5 cells.
AK-5, a rat histiocytoma, is rejected in about 70% of the syngeneic animals when injected subcutaneously. The sera from the tumor rejecting animals possess a potent factor, referred to as serum factor (SF) that induces apoptosis in AK-5 tumor cells. In the present study, we show that treatment with SF or JAK/STAT inhibitors AG490 and Piceatannol induces apoptosis to a similar extent in BC-8 (a single cell clone of AK-5) cells. Our results demonstrate downregulation of a transcription factor, STAT3, as a critical regulator of SF-induced apoptosis in BC-8 cells. SF treatment enhanced the activity of NFkappaB, another transcription factor that regulates both pro- and antiapoptotic genes. The enhanced NFkappaB activity resulted in the elevation of TRAIL and its receptor DR4, both known to induce apoptosis. Activation of death receptors in turn enhances caspase-8 activity and stimulates the downstream pathways regulating BC-8 cell apoptosis. SF induced apoptosis in BC-8 cells mediated through downregulation of STAT3 and elevated NFkappaB activity is abrogated by treatment with MAPK inhibitors-PD98059 and SB203580. Our studies therefore indicate that modulation of MAPK activity plays a central role in SF-induced death signaling pathways in BC-8 cells.
Kumari
A Leela
AL
Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
Ali
A Mubarak
AM
Das
Suvendu
S
Pardhasaradhi
B V V
BV
Varalakshmi
Ch
Ch
Khar
Ashok
A
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D053613:Janus Kinase 1; D008562:Membrane Glycoproteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D053221:TNF-Related Apoptosis-Inducing Ligand; C505655:Tnfsf10 protein, rat; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases