Iuliani Michele, Simonetti Sonia, Ribelli Giulia, Cavaliere Silvia, Vincenzi Bruno, Tonini Giuseppe, Pantano Francesco, Santini Daniele
Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy.
UOC Oncologia Universitaria, Sapienza University of Rome Polo Pontino, 04100 Latina, Italy.
Biomedicines. 2022 Sep 1;10(9):2154. doi: 10.3390/biomedicines10092154.
Abiraterone is a selective inhibitor of androgen biosynthesis approved for the treatment of metastatic patients affected by castration-resistant or castration-sensitive prostate cancer. Intriguingly, clinical data revealed that abiraterone also delayed disease progression in bone improving bone-related endpoints. Our group has previously demonstrated in vitro a direct effect of abiraterone on osteoclast and osteoblast function suggesting its ability to modulate bone microenvironment. Here, we performed an extensive proteomic analysis to investigate how abiraterone influences osteoblast cell secretome and, consequently, osteoblast/prostate cancer cells interaction. A panel of 507 soluble molecules were analyzed in osteoblast conditioned media (OCM) obtained from osteoblast treated or not with abiraterone. Subsequently, OCM was added to prostate cancer cells to investigate its potential effect on prostate cancer cell proliferation and androgen receptor (AR) activation status. Out of 507 screened molecules, 39 of them were differentially expressed in OCM from osteoblasts treated with abiraterone (OCM ABI) compared to OCM obtained from untreated OBs (OCM CTRL). Pathway enrichment analysis revealed that abiraterone down-modulated the release of specific osteoblast soluble factors, positively associated with cell proliferation pathways (false discovery rate adjusted -value = 0.0019). In vitro validation data showed that OCM ABI treatment significantly reduced cancer proliferation in C4-2B cells ( = 0.022), but not in AR- negative PC-3 cells. Moreover, we also found a reduction in AR activation in C4-2B cells ( = 0.017) confirming the "indirect" anti-tumor AR-dependent effect of abiraterone mediated by osteoblasts. This study provides the first evidence of an additional antitumor effect of abiraterone through the modulation of multiple osteoblast proliferative signals.
阿比特龙是一种雄激素生物合成的选择性抑制剂，已被批准用于治疗去势抵抗性或去势敏感性前列腺癌的转移性患者。有趣的是，临床数据显示阿比特龙还能延缓骨转移患者的疾病进展，改善与骨相关的指标。我们团队之前在体外实验中证明了阿比特龙对破骨细胞和成骨细胞功能有直接影响，表明其具有调节骨微环境的能力。在此，我们进行了广泛的蛋白质组学分析，以研究阿比特龙如何影响成骨细胞的分泌组，进而影响成骨细胞/前列腺癌细胞的相互作用。我们分析了从用或未用阿比特龙处理的成骨细胞获得的成骨细胞条件培养基（OCM）中的507种可溶性分子。随后，将OCM添加到前列腺癌细胞中，以研究其对前列腺癌细胞增殖和雄激素受体（AR）激活状态的潜在影响。在筛选的507种分子中，与未处理的成骨细胞（OCM CTRL）获得的OCM相比，用阿比特龙处理的成骨细胞（OCM ABI）的OCM中有39种分子表达存在差异。通路富集分析显示，阿比特龙下调了与细胞增殖通路呈正相关的特定成骨细胞可溶性因子的释放（错误发现率校正P值 = 0.0019）。体外验证数据表明，OCM ABI处理显著降低了C4-2B细胞中的癌细胞增殖（P = 0.022），但对AR阴性的PC-3细胞无此作用。此外，我们还发现C4-2B细胞中的AR激活减少（P = 0.017），证实了阿比特龙通过成骨细胞介导的“间接”抗肿瘤AR依赖性作用。本研究首次证明了阿比特龙通过调节多种成骨细胞增殖信号具有额外的抗肿瘤作用。
