Progesterone sensitizes breast cancer MCF7 cells to imatinib inhibitory effects.
In previous studies, we found that progesterone was able to induce the expression of platelet-derived growth factor (PDGF) in human breast cancer MCF7 cells. Knowing that imatinib mesylate targets PDGF receptor tyrosine kinase activity, the aim of the present study was to examine the effects of imatinib on progesterone-treated MCF7 cells. Expression of phosphorylated (activated) platelet-derived growth factor receptor-alpha (PDGFRalpha) was detected in MCF7 cells. Interestingly, phosphorylated-PDGFRalpha expression was significantly downregulated by imatinib. The effects of imatinib on cell growth, apoptosis and migration were then analyzed. Imatinib effectively inhibited anchorage-dependent colony formation, and cell viability as evaluated by MTT assay. Corroborating these findings, a significant increase in the percentage of apoptotic cells was also observed when cells were treated with imatinib. Surprisingly, these inhibitory effects were all enhanced by the presence of progesterone. Cell migration assays did also show a reduction in the migratory capacity after incubation with imatinib. These findings reveal that imatinib acts by decreasing MCF7 cell viability, growth and migration, with concomitant increase in apoptosis. Furthermore, incubation with progesterone seems to prompt cells to the inhibitory action of imatinib, probably by sustaining PDGFRalpha activity. The current study points out imatinib as a possible therapeutic strategy in progesterone-dependent breast cancer.
Rocha
Ana
A
Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
Azevedo
Isabel
I
Soares
Raquel
R
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011374:Progesterone; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha