Combination of porous Se@SiO2 nanospheres and docetaxel exhibits anti-castration-resistant prostate cancer activity by downregulating ATG14-dependent autophagy

Chemotherapy remains the core anticancer treatment for castration-resistant prostate cancer (CRPC). However, drug resistance still poses a major obstacle, leading to shorter survival times. Given the biosafety of porous Se@SiO 2 nanospheres in normal tissues, their combination with chemotherapeutic drugs has emerged as an effective treatment for cancer. It is unknown whether porous Se@SiO 2 nanospheres can protect CRPC cells from drug resistance. In our study, we synthesized porous Se@SiO 2 nanospheres and confirmed their characteristics in line with previous studies. We discovered that porous Se@SiO 2 nanospheres sensitize CRPC to docetaxel (DTX) treatment, both in vitro and in vivo . Mechanistically, the nanospheres induce dephosphorylation of autophagy-related 14 (ATG14) at Y357 by upregulating the expression of the cellular form of prostatic acid phosphatase (cPAP) protein, which prevents the induction of autophagy and the survival of prostate cancer cells after DTX treatment. Furthermore, there is a negative correlation between cPAP and autophagy in CRPC. Our results suggest that the combination of porous Se@SiO 2 nanospheres with DTX could be a potentially effective treatment for CRPC. Scheme 1. Schematic illustration of a model showing how porous Se@SiO 2 nanospheres confer autophagy to induce DTX sensitivity. Se@SiO 2 upregulates cPAP and stimulates cPAP-dependent dephosphorylation of ATG14 at Y357, which causes ATG14 to disassociate from Beclin1, leading to impairment of the PI3KIII complex. As a consequence, Se@SiO 2 induces autophagy inhibition and DTX sensitivity.