Dataset Information

Proteome profiling of enzalutamide-resistant cell lines and serum analysis identified ALCAM as marker of resistance in castration-resistant prostate cancer

ABSTRACT: Enzalutamide (ENZA) is a frequently used therapy in metastatic castration-resistant prostate cancer (mCRPC). Baseline or acquired resistance to ENZA have been observed, but the molecular mechanisms of resistance are poorly understood. We aimed to identify proteins involved in ENZA resistance and to find therapy-predictive serum markers. We performed comparative proteome analyses on ENZA-sensitive parental (LAPC4, DUCAP) and -resistant prostate cancer cell lines (LAPC4-ENZA, DUCAP-ENZA) using liquid chromatography tandem mass spectrometry (LC-MS/MS). The most promising 4 marker candidates were selected using bioinformatic approaches. Serum concentrations of selected markers (ALCAM, AGR2, NDRG1, IDH1) were measured in 72 ENZA-treated mCRPC patients’ samples using ELISA. In addition, ALCAM serum levels were measured in 101 Abiraterone (ABI) and 100 Docetaxel (DOC)-treated mCRPC patients. Results were correlated with clinical and follow-up data. The functional role of ALCAM in ENZA resistance was assessed in vitro using siRNA. Our proteome analyses revealed 731 significantly differentially abundant proteins between ENZA-sensitive and -resistant cells and our filtering methods identified 4 biomarker candidates. Serum analyses of these proteins revealed only ALCAM to be associated with poor patient survival. Furthermore, higher baseline ALCAM levels were associated with poor survival in ABI- but not in DOC-treated patients. In LAPC4-ENZA resistant cells, ALCAM silencing by siRNA knockdown resulted in significantly enhanced ENZA sensitivity. Our analyses revealed that ALCAM serum levels may help to identify ENZA- and ABI-resistant patients and may thereby help to optimize future clinical decision-making. Our functional analyses suggest the possible involvement of ALCAM in ENZA resistance.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Thilo Bracht

LAB HEAD: Thilo Bracht

PROVIDER: PXD031847 | Pride | 2022-06-24

REPOSITORIES: Pride

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Proteome profiling of enzalutamide-resistant cell lines and serum analysis identified ALCAM as marker of resistance in castration-resistant prostate cancer.

Csizmarik Anita A Keresztes Dávid D Nagy Nikolett N Bracht Thilo T Sitek Barbara B Witzke Kathrin K Puhr Martin M Tornyi Ilona I Lázár József J Takács László L Kramer Gero G Sevcenco Sabina S Maj-Hes Agnieszka A Jurányi Zsolt Z Hadaschik Boris B Nyirády Péter P Szarvas Tibor T

International journal of cancer 20220621 8

Enzalutamide (ENZA) is a frequently used therapy in metastatic castration-resistant prostate cancer (mCRPC). Baseline or acquired resistance to ENZA have been observed, but the molecular mechanisms of resistance are poorly understood. We aimed to identify proteins involved in ENZA resistance and to find therapy-predictive serum markers. We performed comparative proteome analyses on ENZA-sensitive parental (LAPC4, DuCaP) and -resistant prostate cancer cell lines (LAPC4-ENZA, DuCaP-ENZA) using liq ...[more]

PMID: 35689436

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Project description: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. Objective: To identify predictive serum biomarkers for Abi treatment. Design, setting, and participants: 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 methods 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 using ELISA. Moreover, FSCN1 serum concentrations were measured in samples of 69 Docetaxel (Doc) treated mCRPC patients. Outcome measurements and statistical analysis: Serum levels were correlated with patients‘ clinicopathological parameters and survival. Results and limitations: Our proteome analysis identified 68 significantly, at least two-fold upregulated proteins in Abi resistant cells. Using two filtering methods 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. Patient summary: In this study, we identified serum FSCN1 as a marker that may help to predict PCa patients who derive less benefit from Abi but not Doc treatment.

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