Comparative proteome and serum analysis identified FSCN1 as a marker of abiraterone resistance in castration-resistant prostate cancer,Prostate Cancer and Prostatic Diseases

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Comparative proteome and serum analysis identified FSCN1 as a marker of abiraterone resistance in castration-resistant prostate cancer
Prostate Cancer and Prostatic Diseases ( IF 5.1 ) Pub Date : 2023-08-26 , DOI: 10.1038/s41391-023-00713-y
Anita Csizmarik ₁ , Nikolett Nagy ₁ , Dávid Keresztes _{1,

2} , Melinda Váradi ₁ , Thilo Bracht _{3,

4,

5} , Barbara Sitek _{3,

4,

5} , Kathrin Witzke _{3,

5} , Martin Puhr ₆ , Ilona Tornyi ₇ , József Lázár ₇ , László Takács _{7,

8} , Gero Kramer ₉ , Sabina Sevcenco ₉ , Agnieszka Maj-Hes ₉ , Boris Hadaschik ₁₀ , Péter Nyirády ₁ , Tibor Szarvas _{1,

10}

Affiliation

Background

Abiraterone (Abi) is an androgen receptor signaling inhibitor that significantly improves patients’ life expectancy in metastatic prostate cancer (PCa). Despite its beneficial effects, many patients have baseline or acquired resistance against Abi. The aim of this study was to identify predictive serum biomarkers for Abi treatment.

Methods

We performed a comparative proteome analysis on three Abi sensitive (LNCaPabl, LAPC4, DuCaP) and resistant (LNCaPabl-Abi, LAPC4-Abi, DuCaP-Abi) PCa cell lines using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Two bioinformatic selection workflows were applied to select the most promising candidate serum markers. Serum levels of selected proteins were assessed in samples of 100 Abi-treated patients with metastatic castration-resistant disease (mCRPC) using ELISA. Moreover, FSCN1 serum concentrations were measured in samples of 69 Docetaxel (Doc) treated mCRPC patients.

Results

Our proteome analysis identified 68 significantly, at least two-fold upregulated proteins in Abi resistant cells. Using two filtering workflows four proteins (AMACR, KLK2, FSCN1 and CTAG1A) were selected for ELISA analyses. We found high baseline FSCN1 serum levels to be significantly associated with poor survival in Abi-treated mCRPC patients. Moreover, the multivariable analysis revealed that higher ECOG status (>1) and high baseline FSCN1 serum levels (>10.22 ng/ml by ROC cut-off) were independently associated with worse survival in Abi-treated patients (p < 0.001 and p = 0.021, respectively). In contrast, no association was found between serum FSCN1 concentrations and overall survival in Doc-treated patients.

Conclusions

Our analysis identified baseline FSCN1 serum levels to be independently associated with poor survival of Abi-treated, but not Doc-treated mCRPC patients, suggesting a therapy specific prognostic value for FSCN1.

中文翻译：

比较蛋白质组和血清分析确定 FSCN1 是去势抵抗性前列腺癌阿比特龙抵抗的标志物

背景

阿比特龙 (Abi) 是一种雄激素受体信号抑制剂，可显着延长转移性前列腺癌 (PCa) 患者的预期寿命。尽管具有有益的作用，但许多患者对 Abi 具有基线或获得性耐药性。本研究的目的是确定 Abi 治疗的预测性血清生物标志物。

方法

我们使用液相色谱串联质谱 (LC-MS/MS) 技术对三种 Abi 敏感（LNCaPabl、LAPC4、DuCaP）和耐药（LNCaPabl-Abi、LAPC4-Abi、DuCaP-Abi）PCa 细胞系进行了比较蛋白质组分析。应用两种生物信息学选择工作流程来选择最有希望的候选血清标记物。使用 ELISA 评估 100 名接受 Abi 治疗的转移性去势抵抗性疾病 (mCRPC) 患者样本中选定蛋白质的血清水平。此外，还测量了 69 名接受多西他赛 (Doc) 治疗的 mCRPC 患者样本中的 FSCN1 血清浓度。

结果

我们的蛋白质组分析鉴定出 Abi 抗性细胞中 68 种显着、至少两倍上调的蛋白质。使用两种过滤工作流程，选择四种蛋白质（AMACR、KLK2、FSCN1 和 CTAG1A）进行 ELISA 分析。我们发现高基线 FSCN1 血清水平与 Abi 治疗的 mCRPC 患者的生存率低显着相关。此外，多变量分析显示，较高的 ECOG 状态 (>1) 和较高的基线 FSCN1 血清水平（根据 ROC 截止值>10.22 ng/ml）与 Abi 治疗患者的较差生存率独立相关（ p < 0.001 和p =分别为 0.021）。相比之下，在 Doc 治疗的患者中，血清 FSCN1 浓度与总生存期之间没有发现关联。