Butyrylcholinesterase (BChE) downregulation in taxane resistance: implications for prostate cancer

Abstract

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. Materials and methods: In transcriptome (RNA sequencing) analyses comparing taxane-resistant PC cells (resistant to both Dtx and Cbz) with parental (nonresistant, sensitive) cells, butyrylcholinesterase (BChE) 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 BChE 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. Results: 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 BChE mRNA levels in patient samples across various cancers, including PC. Additionally, The Cancer Genome Atlas (TCGA) analyses identified BChE as a significant posttreatment neoplasm marker in PC. Conclusion: Our study confirmed the downregulation of BChE 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.