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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.
- Source :
-
Endocrinology [Endocrinology] 2008 Aug; Vol. 149 (8), pp. 3789-98. Date of Electronic Publication: 2008 May 08. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Female
Humans
MAP Kinase Signaling System drug effects
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase C antagonists & inhibitors
Protein Kinase C metabolism
Protein Kinase Inhibitors pharmacology
RNA, Small Interfering pharmacology
Tumor Cells, Cultured
X-Linked Inhibitor of Apoptosis Protein antagonists & inhibitors
X-Linked Inhibitor of Apoptosis Protein metabolism
Apoptosis drug effects
Carcinoma pathology
Drug Resistance, Neoplasm drug effects
Endometrial Neoplasms pathology
Protein Kinase C physiology
Tumor Necrosis Factor-alpha pharmacology
X-Linked Inhibitor of Apoptosis Protein physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0013-7227
- Volume :
- 149
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 18467439
- Full Text :
- https://doi.org/10.1210/en.2008-0275