Cevatemre Buse, Işiklar Arda, Bulut İpek, Karyemez Ezgi, Syed Hamzah, Açilan Ceyda
Division of Medical Biology, Faculty of Medicine, Koç University, İstanbul, Turkiye.
Research Center for Translational Medicine, Koç University, İstanbul, Turkiye.
Turk J Biol. 2025 Mar 26;49(3):261-272. doi: 10.55730/1300-0152.2743. eCollection 2025.
BACKGROUND/AIM: Despite advancements in chemotherapeutic strategies, drug resistance remains a major barrier to effective cancer treatment. While primary prostate cancers (PC) can be treated with surgery and radiotherapy, treatment options for recurrent PC are limited. Upon progression to the castration-resistant (CR) phase, therapies rely on taxanes (chemotherapeutic drugs) like docetaxel (Dtx) and cabazitaxel (Cbz); however, resistance to taxanes is common in CRPC, highlighting the importance of identifying underlying molecular mechanisms or targets in resistant cells.
In transcriptome (RNA sequencing) analyses comparing taxane-resistant PC cells (resistant to both Dtx and Cbz) with parental (nonresistant, sensitive) cells, butyrylcholinesterase () was identified as the most significantly downregulated gene. Although low serum BChE levels have been documented in various cancers, its role in chemotherapy resistance remains unclear. To address this gap, we validated its expression in taxane-resistant CRPC lines and manipulated levels in both parental and resistant cells via lentiviral overexpression or depletion using shRNA and gRNA (CRISPR-Cas9), to assess its impact on taxane resistance.
BChE suppression in parental CRPC cells conferred resistance, whereas its overexpression in taxane-resistant cells was insufficient to resensitize them. Analysis of publicly available databases showed reduced mRNA levels in patient samples across various cancers, including PC. Additionally, The Cancer Genome Atlas (TCGA) analyses identified as a significant posttreatment neoplasm marker in PC.
Our study confirmed the downregulation of in taxane-resistant CRPC cell models and established its role in conferring resistance when depleted in parental CRPC cells, highlighting its association with taxane resistance. Additionally, the identification of BChE as a posttreatment neoplasm marker, derived from data mining analyses, suggests it might serve as a biomarker for tracking disease progression in PC.
背景/目的：尽管化疗策略取得了进展，但耐药性仍然是有效癌症治疗的主要障碍。虽然原发性前列腺癌（PC）可以通过手术和放疗进行治疗，但复发性PC的治疗选择有限。在进展到去势抵抗（CR）阶段后，治疗依赖于紫杉烷类（化疗药物），如多西他赛（Dtx）和卡巴他赛（Cbz）；然而，CRPC中对紫杉烷类耐药很常见，这凸显了识别耐药细胞中潜在分子机制或靶点的重要性。
在转录组（RNA测序）分析中，将紫杉烷耐药的PC细胞（对Dtx和Cbz均耐药）与亲代（非耐药、敏感）细胞进行比较，丁酰胆碱酯酶（）被确定为下调最显著的基因。尽管在各种癌症中都有低血清BChE水平的记录，但其在化疗耐药中的作用仍不清楚。为了填补这一空白，我们在紫杉烷耐药的CRPC细胞系中验证了其表达，并通过慢病毒过表达或使用shRNA和gRNA（CRISPR-Cas9）进行缺失操作，在亲代和耐药细胞中调控其水平，以评估其对紫杉烷耐药性的影响。
亲代CRPC细胞中BChE的抑制赋予了耐药性，而其在紫杉烷耐药细胞中的过表达不足以使其重新敏感。对公开可用数据库的分析显示，包括PC在内的各种癌症患者样本中的mRNA水平降低。此外，癌症基因组图谱（TCGA）分析确定其为PC中一个重要的治疗后肿瘤标志物。
我们的研究证实了在紫杉烷耐药的CRPC细胞模型中BChE的下调，并确定了其在亲代CRPC细胞中缺失时赋予耐药性的作用，突出了其与紫杉烷耐药性的关联。此外，通过数据挖掘分析将BChE鉴定为治疗后肿瘤标志物，表明它可能作为PC中追踪疾病进展的生物标志物。
