Frontiers in pharmacology · 2026
CRIP1 promotes docetaxel resistance and immune-associated cell death modulation in prostate cancer.
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Zhang Dehua, Han Meiling, Yan Ni, Zhang Yu, Wang Chao, Shi Wenzhong, Jia Wenxue, Cao Jun
Аннотация
BACKGROUND: Docetaxel resistance is a major barrier to durable disease control in advanced and castration-resistant prostate cancer. There is a pharmacological need to identify biomarkers that not only stratify resistance risk but also nominate tractable regulators whose perturbation can restore taxane sensitivity and suppress resistant phenotypes.
METHODS: We analyzed docetaxel-resistant prostate cancer cell models to derive resistance-associated transcriptional candidates and used computational prioritization to construct a compact, taxane-resistance-anchored gene set. Associations of the gene set and key candidates with disease progression were evaluated in TCGA-PRAD, which predominantly represents treatment-naïve primary tumors and therefore provides progression relevance rather than treatment-specific response validation. Docetaxel-resistant cell lines were established for functional validation, and CRIP1 was stably silenced to assess effects on drug sensitivity, clonogenic growth, migration, apoptosis, and immune-associated cell-death features. In addition, an LNCaP-DTXr xenograft model was used to evaluate the impact of CRIP1 knockdown on docetaxel response in vivo.
RESULTS: A three-gene, taxane-resistance-anchored signature was derived and showed progression-related associations in TCGA-PRAD. Among candidates, cysteine-rich protein 1 (CRIP1) was consistently upregulated in resistant models and emerged as a top resistance-associated factor. Functionally, CRIP1 knockdown restored docetaxel sensitivity, reduced clonogenic survival and migratory capacity, and enhanced docetaxel-induced apoptosis in resistant prostate cancer cells. Consistently, CRIP1 depletion significantly suppressed tumor growth and reduced tumor burden in docetaxel-treated LNCaP-DTXr xenografts, indicating restored chemosensitivity in vivo. In parallel, CRIP1 depletion was accompanied by changes in damage-associated and immune-related cell-death readouts under taxane stress, suggesting a potential role in linking drug tolerance to immune-relevant cell-death programs.
CONCLUSION: These findings identify CRIP1 as a functionally validated, pharmacologically relevant mediator of docetaxel resistance in prostate cancer. While independent validation in taxane-treated clinical cohorts is warranted, our results support CRIP1 as a candidate therapeutic target and provide a mechanistic framework connecting taxane resistance with immune-associated cell-death modulation.
METHODS: We analyzed docetaxel-resistant prostate cancer cell models to derive resistance-associated transcriptional candidates and used computational prioritization to construct a compact, taxane-resistance-anchored gene set. Associations of the gene set and key candidates with disease progression were evaluated in TCGA-PRAD, which predominantly represents treatment-naïve primary tumors and therefore provides progression relevance rather than treatment-specific response validation. Docetaxel-resistant cell lines were established for functional validation, and CRIP1 was stably silenced to assess effects on drug sensitivity, clonogenic growth, migration, apoptosis, and immune-associated cell-death features. In addition, an LNCaP-DTXr xenograft model was used to evaluate the impact of CRIP1 knockdown on docetaxel response in vivo.
RESULTS: A three-gene, taxane-resistance-anchored signature was derived and showed progression-related associations in TCGA-PRAD. Among candidates, cysteine-rich protein 1 (CRIP1) was consistently upregulated in resistant models and emerged as a top resistance-associated factor. Functionally, CRIP1 knockdown restored docetaxel sensitivity, reduced clonogenic survival and migratory capacity, and enhanced docetaxel-induced apoptosis in resistant prostate cancer cells. Consistently, CRIP1 depletion significantly suppressed tumor growth and reduced tumor burden in docetaxel-treated LNCaP-DTXr xenografts, indicating restored chemosensitivity in vivo. In parallel, CRIP1 depletion was accompanied by changes in damage-associated and immune-related cell-death readouts under taxane stress, suggesting a potential role in linking drug tolerance to immune-relevant cell-death programs.
CONCLUSION: These findings identify CRIP1 as a functionally validated, pharmacologically relevant mediator of docetaxel resistance in prostate cancer. While independent validation in taxane-treated clinical cohorts is warranted, our results support CRIP1 as a candidate therapeutic target and provide a mechanistic framework connecting taxane resistance with immune-associated cell-death modulation.