Smoothened Antagonists Reverse Taxane Resistance in Ovarian Cancer
Menée in vitro et à l'aide de xénogreffes, cette étude évalue les effets d'un antagoniste du récepteur Smoothened de la voie de signalisation Hedgehog sur la réponse à une chimiothérapie à base de taxanes dans le cancer de l'ovaire
Résumé en anglais
The hedgehog (HH) pathway has been implicated in the formation and maintenance of a variety of malignancies, including ovarian cancer; however, it is unknown whether HH signaling is involved in ovarian cancer chemoresistance. The goal of this study was to determine the effects of antagonizing the HH receptor, Smoothened (Smo), on chemotherapy response in ovarian cancer. Expression of HH pathway members was assessed in 3 pairs of parental and chemotherapy-resistant ovarian cancer cell lines (A2780ip2/A2780cp20, SKOV3ip1/SKOV3TRip2, HeyA8/HeyA8MDR) using qPCR and Western blot. Cell lines were exposed to increasing concentrations of two different Smo antagonists (cyclopamine, LDE225) alone and in combination with carboplatin or paclitaxel. Selective knockdown of Smo, Gli1 or Gli2 was achieved using siRNA constructs. Cell viability was assessed by MTT assay. A2780cp20 and SKOV3TRip2 orthotopic xenografts were treated with vehicle, LDE225, paclitaxel or combination therapy. Chemoresistant cell lines demonstrated higher expression (>2-fold, p<0.05) of HH signaling components compared to their respective parental lines. Smo antagonists sensitized chemotherapy-resistant cell lines to paclitaxel, but not to carboplatin. LDE225 treatment also increased sensitivity of ALDH-positive cells to paclitaxel. A2780cp20 and SKOV3TRip2 xenografts treated with combined LDE225 and paclitaxel had significantly less tumor burden than those treated with vehicle or either agent alone. Increased taxane sensitivity appeared to be mediated by a decrease in P-glycoprotein (MDR1) expression. Selective knockdown of Smo, Gli1 or Gli2 all increased taxane sensitivity. Smo antagonists reverse taxane resistance in chemoresistant ovarian cancer models, suggesting combined anti-HH and chemotherapies could provide a useful therapeutic strategy for ovarian cancer.
