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| HER2 signaling downregulation by trastuzumab and suppression of the PI3K/Akt pathway: An unexpected effect on TRAIL-induced apoptosis |
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| Author(s): Dubska L, Andera L, Sheard MA |
| Source: FEBS LETTERS Volume: 579 Issue: 19 Pages: 4149-4158 Published: AUG 1 2005 |
| Times Cited: 9 References: 61 |
| Abstract: We investigated whether HER2 downregulation by trastuzumab modulates the responsiveness of breast cancer cells to TNF-related apoptosis-inducing ligand (TRAIL). Interestingly, in contrast to increased response to TRAIL in SKBr3 cells, trastuzumab decreased the susceptibility of BT474 cells to TRAIL. This decrease was also observed after exogenous inhibition of P13-K/Akt kinase, but not MAPK/ERK kinase (MEK)/mitogen-activated protein kinase (MAPK). In BT474 cells, but not SKBr3 cells, inhibition of the HER2/phosphatidylinositol 3' kinase (PI3K)/Akt pathway resulted in downregulation of the pro-apoptotic receptors TRAIL-receptor 1 (TRAIL-R1) and TRAIL-R2. TRAIL-induced caspase-8 activation, Bid processing, drop of AT., and poly ADP-ribose polymerase (PARP) cleavage but not in caspase-9 activation, and these events were inhibited in HER2/PI3K/Akt-suppressed BT474 cells, which on the other hand exhibited downregulation of BCl-X-L and increased response to mitomycin C. We show that HER2/PI3K/Akt pathway may play a specific pro-apoptotic role in certain cell type by inducing TRAIL-R1 and -R2 expression and thereby enhancing responsiveness to TRAIL. (c) 2005 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. |
| Document Type: Article |
| Language: English |
| Reprint Address: Dubska, L (reprint author), Masaryk Mem Canc Inst, Dept Lab Med, Zluty Kopec 7, Brno 65653, Czech Republic |
Addresses:
1. Masaryk Mem Canc Inst, Dept Lab Med, Brno 65653, Czech Republic
2. Masaryk Univ, Dept Genet & Mol Biol, Brno, Czech Republic
3. Acad Sci Czech Republ, Inst Mol Genet, Prague, Czech Republic
4. Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA |
| Publisher: ELSEVIER SCIENCE BV, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS |
| Subject Category: Biochemistry & Molecular Biology; Biophysics; Cell Biology |
| IDS Number: 951ZP |
| ISSN: 0014-5793 |
| DOI: 10.1016/j.febslet.2005.06.047 |
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