Abstract
Background: System paclitaxel-based chemotherapy is the first-line treatment regimen of defense against breast cancer, but inherent or acquired chemotherapy resistance remains a major obstacle in breast cancer therapy. Elucidating the molecular mechanism of chemoresistance is essential to improve the outcome of patients with breast cancer.
Methods: Paclitaxel sensitivity was first evaluated using models of IFT20 deletion and overexpression of breast cancer cells in vitro and in vivo studies to identify the effect of IFT20 on paclitaxel chemoresistance. To delineate the molecular mechanism of IFT20 contributions to paclitaxel chemoresistance, changes in ASK signaling and its downstream JNK cascades expression were quantified using western blots, and the potential involvement of β-arrestin-1 was investigated using co-IP studies.
Results: IFT20 is positively associated with shorter relapse-free survival in patients with system paclitaxel-based chemotherapy. High expressed IFT20 in breast cancer cells increases resistance to cell death upon paclitaxel treatment; in contrast, IFT20 knockdown enhances apoptosis in breast cancer cells in response to paclitaxel. Mechanistically, IFT20 triggers β-arrestin-1 to bind with ASK1 and promotes the ubiquitination of ASK1 degradation, leading to attenuating ASK1 signaling and its downstream JNK cascades, which helped cells to escape from cell death during paclitaxel treatment.
Conclusion: IFT20 confers to paclitaxel chemoresistance. It interacts with β-arrestin-1 to mediate ubiquitination of ASK1 for feedback inhibition of ASK1/JNK signaling and restrains paclitaxel-induced apoptosis. These findings identify IFT20 as a promising novel target for overcoming paclitaxel resistance in breast cancer.
The molecular mechanism of chronic stress affecting the occurrence and development of breast cancer and potential drug therapy
