多西他赛是治疗去势抵抗性前列腺癌(CRPC)的一线化疗药，但仍面临耐药性的困扰。含硒纳米材料可抑制多种肿瘤生长，其机制尚不明确，与多西他赛联用也未见报道。申请人课题组前期合成了具有高生物安全性及肿瘤靶向性的二氧化硅纳米硒（Se@SiO2），并发现其可改善因自噬引起的多西他赛耐药，减少CRPC细胞增殖；进一步研究表明Se@SiO2可增强细胞内肿瘤抑制因子cPAP的蛋白稳定性；我们发现cPAP作为一种酪氨酸磷酸酶可去磷酸化ATG14抑制自噬起始，进而抑制CRPC；并初步鉴定出可能的磷酸化位点（Y279/Y357/Y488）。基于此我们提出Se@SiO2通过上调cPAP-ATG14通路抑制自噬并增敏多西他赛治疗CRPC。本研究将进一步验证Se@SiO2联合多西他赛对CRPC的治疗作用，阐明Se@SiO2通过cPAP调控自噬的分子机制。本课题为改善CRPC化疗耐药提供了新的治疗思路和理论依据。

Docetaxel is the first-line chemotherapy agent for castration-resistant prostate cancer (CRPC), but resistance to docetaxel remains a problem. Though selenium nano-particles are reported to inhibit tumor growth, the mechanisms are still not clear. Moreover, no combination therapy of selenium nanocomposites with docetaxel has been applied yet. Based on our previous work，porous selenium nanocomposites (Se@SiO2) with high biosafety and tumor-targeting properties were synthesized. Se@SiO2 could reduce proliferation and autophagy level in CRPC cells. Furthermore, our results showed that Se@SiO2 could enhance the protein stability of intracellular prostate acid phosphatase (cPAP). As a tyrosine phosphatase, cPAP blocks the initiation of autophagy by promoting ATG14 dephosphorylation, thereby reducing the proliferation of CRPC cells. In addition, three possible tyrosine phosphorylation sites (Y279/Y357/Y488) were identified using site-directed mutagenesis. Accordingly, we hypothesized that Se@SiO2 sensitizes Docetaxel in CRPC treatment through inhibiting autophagy by activating cPAP-ATG14 signaling axis. This study will further verify the therapeutic effect of Se@SiO2 combined with docetaxel on CRPC, and elucidate the molecular mechanism of Se@SiO2 regulating autophagy through cPAP. Our research provides a new therapeutic option and theoretical evidence for the treatment of CRPC chemotherapy resistance.