The Relationship between Gene Status and Carboxylesterase 2 Expression in Human Colorectal Cancer.

Irinotecan (CPT-11) is an anticancer prodrug that is activated by the carboxylesterase CES2 and has been approved for the treatment of many types of solid tumors, including colorectal cancer. Recent studies with cell lines show that CES2 expression is regulated by the tumor suppressor protein p53. However, clinical evidence for this regulatory mechanism in cancer is lacking. In this study, we examined the relationship between gene status and CES2 expression in human colorectal cancer. Most colorectal cancer specimens (70%; 26 of 37) showed lower CES2 mRNA levels (≥1.5-fold lower) than the adjacent normal tissue, and only 30% (12 of 37) showed similar (<1.5-fold lower) or higher CES2 mRNA levels. However, gene sequencing revealed no relationship between CES2 downregulation and mutational status. Moreover, while colorectal cancer cells expressing wild-type p53 exhibited p53-dependent upregulation of CES2, PRIMA-1, a drug that restores the transcriptional activity of mutant p53, failed to upregulate CES2 expression in cells with missense mutations. These results, taken together, suggest that CES2 mRNA expression is decreased in human colorectal cancer independently of p53.