ARTS confers chemoresistance of breast cancer by inducing apoptosis-dependent autophagy via Livin-MDM2-p53 pathway

Apoptosis and autophagy are two fundamental pathophysiological processes of cell fate regulation under stress conditions, especially in anti-cancer therapy. However, the interplay between apoptosis and autophagy in the cancer chemoresistance is not fully elucidated. Herein, we identified apoptosis-related protein in TGF-ß signaling pathway (ARTS) as a key link between apoptosis and autophagy, facilitating cell survival and chemoresistance. ARTS was highly expressed in chemoresistant breast cancer tissues and was associated with patient poor prognosis. Expression of ARTS conferred the resistance of doxorubicin (DOX) and docetaxel (DTX) by inducing autophagy in breast cancer cells in vivo and in vitro. As regards the mechanism of action, ARTS translocated from the mitochondrial intermembrane space to the cytoplasm after pro-apoptotic signals from chemotherapeutic drugs, subsequently inducing autophagy through the SIAH1-mediated Livin degradation and further activation of the MDM2/p53 pathway, thus resulting in the survival of breast cancer cells. The inhibition of apoptosis or autophagy effectively suppressed the chemoresistance mediated by ARTS. Generally, this study identified a new pathway of ARTS/Livin/MDM2/p53 conferred chemoresistance of breast cancer through inducing autophagy in an apoptosis-dependent manner. Overall design: For pre- and post-chemotherapy breast cancer HE-stained sections, histological responses were evaluated by two pathologists according to the Miller-Payne Grading (MPG) system. Among the pre-chemotherapy samples submitted, five were classified as Grade 1 (G1) and five as Grade 5 (G5). These samples were utilized to assess genes associated with chemotherapy resistance.