X-linked inhibitor of apoptosis protein levels and protein kinase C activity regulate the sensitivity of human endometrial carcinoma cells to tumor necrosis factor alpha-induced apoptosis.
Endometrial carcinomas are often chemoresistant. TNFalpha shows potent antitumor activity against various cancers, and if it demonstrates good antitumor activity against endometrial cancer, the cytokine could represent a valuable alternative therapeutic approach. We have tested the ability of TNFalpha to induce apoptosis in endometrial carcinoma cells, and examined a putative role for X-linked inhibitor of apoptosis protein (XIAP) in regulating cellular sensitivity to the cytokine. Exposure to TNFalpha triggered TNF-R1-dependent activation of caspases-8, -9, and -3, down-regulated Akt and XIAP proteins and induced dose-dependent and time-dependent apoptosis in Ishikawa cells. On the opposite, TNFalpha up-regulated XIAP in Hec-1A cells; in these cells, the cytokine induced delayed TNF-R1-dependent activation of caspase-8, and failed to activate caspases -9 and -3 and to induce apoptosis. However, XIAP small interfering RNA restored TNFalpha-induced caspase signaling and apoptosis in Hec-1A cells; XIAP small interfering RNA also increased TNFalpha-induced apoptosis in Ishikawa cells. In addition, inhibition of protein kinase C activity enhanced TNFalpha-induced down-regulation of XIAP and potentiated apoptosis induction, in both Ishikawa and Hec-1A cells. Finally, we found XIAP immunoreactivity in epithelial cells from a large number of human endometrial tumor tissue samples, indicating that XIAP is produced by endometrial tumor cells in vivo. This could allow XIAP to play a putative in vivo role in counteracting TNFalpha-induced apoptosis in endometrial tumor cells; in this case, direct or indirect targeting of XIAP should potentiate the antitumor effect of TNFalpha.
Van Themsche
Céline
C
Research Group in Molecular Oncology and Endocrinology, Department of Chemistry and Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada G9A 5H7.
Lafontaine
Lyne
L
Asselin
Eric
E
D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D011493:Protein Kinase C