IFT20 Confers Paclitaxel Resistance by Triggering b-arrestin-1 to Modulate ASK1 Signaling in Breast Cancer

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. Here, we demonstrate that intraflagellar transport 20 (IFT20) is positively associated with shorter relapse-free survival in pati-ents 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 apo-ptosis in breast cancer cells in response to paclitaxel. Mechanistically, IFT20 triggers (3-arrestin-1 to bind with apoptosis signal-regulating kinase 1 (ASK1) and promotes the ubiquitination of ASK1 degra-dation, leading to attenuating ASK1 signaling and its downstream JNK cascades, which helps cells to escape from cell death during paclitaxel treatment. Our results reveal that IFT20 drives pacli-taxel resistance through modulating ASK1 signaling and identi-fies IFT20 as a potential molecular biomarker for predicting the response to paclitaxel therapeutic in breast cancer. Implications: IFT20 drives paclitaxel resistance through modulat-ing ASK1 signaling and IFT20 may act as a potential molecular biomarker for predicting the response to paclitaxel therapeutic in breast cancer.

Automated summary

System paclitaxel-based chemotherapy is the first-line treatment for breast cancer, but chemotherapy resistance remains a major challenge. Our study shows that IFT20 is associated with shorter relapse-free survival in patients receiving paclitaxel chemotherapy. High expression of IFT20 in breast cancer cells increases resistance to paclitaxel-induced cell death, while IFT20 knockdown enhances apoptosis. Mechanistically, IFT20 modulates ASK1 signaling to drive paclitaxel resistance. IFT20 may serve as a potential molecular biomarker for predicting response to paclitaxel therapy in breast cancer.