Apoptotic effects of signal transduction inhibitors on human tumor cells with different PTEN expression.
An important mechanism of antitumoral targeted therapies is the induction of apoptosis in tumor cells. Tamoxifen and trastuzumab (Herceptin), respectively, are able to trigger apoptosis in human breast cancer cells. But, frequently altered apoptotic signal cascades, for instance through PTEN mutations, help tumor cells to escape antitumoral therapy. We studied to what extent the apoptotic effect of signal-transduction inhibitors is dependent on PTEN expression. PTEN expression was analysed by Western blot analysis in tumor cell lines of the breast (BT-474, MCF-7, MDA-MB-231), ovary (BG-1, SK-OV-3) and endometrium (Ishikawa, HEC-1A). Apoptotic effects of tamoxifen, trastuzumab, ZD1839 (Iressa) and different mitogen-activated protein kinase (MAP) inhibitors were measured after 24 h of treatment. Cellular apoptosis was determined by the detection of cytoplasmic histone-DNA complexes. The tested tumor cell lines exhibited a different PTEN expression, ranging from a high expression (ovarian cancer cell line BG-1 and BT-474 breast cancer cells) to a total absence of PTEN expression (endometrial Ishikawa cells). The apoptotic effect of receptor-targeting drugs (tamoxifen, trastuzumab, ZD1839) was dependent both on receptor expression and PTEN expression. When cells were treated with MAPK inhibitors, no correlation between PTEN expression and the apoptosis rate was observed. Our data underline the importance of PTEN expression regarding the induction of apoptosis through various targeted therapies.
Pfeiler
Georg
G
Department of Obstetrics and Gynecology, University of Regensburg, Caritas Hospital St. Josef, Landshuter Strasse 65, 93053 Regensburg, Germany.
Horn
Felicitas
F
Lattrich
Claus
C
Klappenberger
Stefanie
S
Ortmann
Olaf
O
Treeck
Oliver
O
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D000077156:Gefitinib; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D005419:Flavonoids; D011799:Quinazolines; D013629:Tamoxifen; C512478:EGFR protein, human; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077156:Gefitinib; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one