ARTS Confers Chemoresistance of Breast Cancer by Inducing Apoptosis-Dependent Autophagy via Livin-MDM2-p53 Pathway

Apoptosis and autophagy are fundamental pathophysiological programs governing cell fate decisions under stress, particularly during anticancer therapy. However, the interplay between apoptosis and autophagy in cancer chemoresistance remains incompletely understood. Here, we identify the apoptosis-related protein in the transforming growth factor-β signaling pathway (ARTS) as a key molecular transferring apoptotic signal to autophagic machinery to promote cell survival and chemoresistance. ARTS was highly expressed in chemoresistant breast cancer tissues and was associated with poor patient prognosis. ARTS conferred resistance to doxorubicin and docetaxel by inducing protective autophagy in vitro and in vivo cancer models. Mechanistically, upon proapoptotic signaling triggered by chemotherapeutic agents, ARTS translocated from the mitochondrial intermembrane space into the cytosol, where it induced autophagy through triggering seven in absentia homolog 1-mediated degradation of Livin and subsequent engagement of the mouse double minute 2 homolog (MDM2)-p53 axis, thereby promoting cancer cell survival. Pharmacologic inhibition of caspases or autophagic flux attenuated ARTS-mediated chemoresistance. Overall, this study delineates an apoptosis-dependent ARTS-Livin-MDM2-p53 pathway that drives autophagy and confers chemoresistance in breast cancer.