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 TP53 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, TP53 gene sequencing revealed no relationship between CES2 downregulation and TP53 mutational status. Moreover, while colorectal cancer cells expressing wild-type p53 exhibited p53-dependent upregulation of CES2, PRIMA-1MET, a drug that restores the transcriptional activity of mutant p53, failed to upregulate CES2 expression in cells with TP53 missense mutations. These results, taken together, suggest that CES2 mRNA expression is decreased in human colorectal cancer independently of p53.
Malignant mesothelioma (MM) is an aggressive malignant neoplasm which rapidly invades pleural tissues and has a poor prognosis. Here, we explore enhancement of the effect of irinotecan [camptothecin-11 (CPT-11)] by the p53-dependent induction of carboxylesterase 2 (CES2), a CPT-11-activating enzyme, in MM. The level of CES2 mRNA was greatly increased on treatment with nutlin-3a. A combination of CPT-11 and nutlin-3a inhibited the growth of MM cells more effectively than either drug alone. Knocking down CES2 in MM cells reduced the effect of the drug combination, and its forced expression in MESO4 cells enhanced the growth inhibitory activity of CPT-11 in the absence of nutlin-3a. Enhancement of the growth inhibitory activity of CPT-11 by nutlin-3a suggests a possible new combinatorial MM chemotherapy regimen. Malignant mesotheliomas (MMs) are rare fatal malignancies associated with the exposure to asbestos, con-stituting~0.2% of all newly diagnosed malignancies [1]. MMs originate from mesothelial cells and fall into three main subtypes, epithelioid, sarcomatoid, and biphasic, according to the histological phenotype [2]. MMs of the sarcomatoid subtype have an exceptionally poor prognosis [3]. Most MM patients have unresectable disease, and therefore, different anticancer drug regimens have been tested in clinical trials.
Carboxylesterases (CESs) play important roles in the metabolism of prodrugs containing ester bonds, which are often introduced to improve bioavailability and drug efficacy. CES1 and CES2 are major isozymes encoded by genes in the CES multigene family in humans, and their characteristics such as tissue distribution and substrate specificity have been extensively studied over the past few decades. This mini review briefly summarizes the current knowledge on CES2 focusing on its roles in the metabolism of anticancer prodrugs. We also discuss the regulatory mechanism of CES2 expression, which is often dysregulated in cancer cells. The development of CES2 inhibitors and methods to evaluate CES2 activity in biological samples are also discussed.
Carboxylesterases are serine hydrolases that are involved in the metabolisms of various endogenous and exogenous compounds. They are also required for activation of many anti-cancer prodrugs. For example, irinotecan (CPT-11), an anti-cancer prodrug that has been approved for the treatment of many types of solid tumors including gastric cancer, is converted by the carboxylesterase CES2 to its active metabolite 7-ethyl-10-hydroxycamptothesin (SN-38), a very potent topoisomerase I inhibitor. Among carboxylesterase isozymes, CES2 is most highly expressed in the gastrointestinal tract. Thus, the expression of CES2 may play an important role in local (i.e., intratumoral) activation of anti-cancer prodrugs such as irinotecan in the gut. Recent studies with cultured cancer cell lines have shown that CES2 expression is regulated by the tumor suppressor protein p53. However, whether CES2 expression is affected by the presence of p53 mutation in clinical cancer samples still remains unclear. In this study, we focused on the regulatory mechanism of CES2 expression in gastric cancer. First, we examined the relationship between TP53 gene status and CES2 expression using gastric cancer cell lines. Several gastric cancer cell lines expressing wild-type p53 (AGS, NUGC4, MKN74, and HSC58) were treated with nutlin-3a, a drug that inhibits the interaction between p53 and the E3 ubiquitin ligase MDM2 and thereby directly activates p53 signaling without genotoxic side effects. The expression of p21, a downstream target of p53, was increased following nutlin-3a treatment in two p53 wild-type cell lines NUGC4 and HSC58. The expression of CES2 was also upregulated by nutlin-3a in three p53 wild-type cell lines AGS, NUGC4, and HSC58. As expected, the expression levels of p21 and CES2 were not largely affected by nutlin-3a in gastric cancer cell lines with TP53 mutations. These results indicate that CES2 expression is positively regulated by the p53 pathway in most gastric cancer cells. We also investigated the relationship between TP53 gene status and CES2 expression in human gastric cancer samples. Our results may provide useful information for predicting the efficacy of anti-cancer prodrugs that are activated by CES2 in gastric cancer. Note: This abstract was not presented at the meeting. Citation Format: Yoshinori Kohira, Hyeon-Cheol Lee, Momoko Ishimine, Hajime Orita, Toshiyuki Kobayashi, Koichi Sato, Takehiko Yokomizo, Tetsu Fukunaga. The relationship between TP53 gene status and carboxylesterase 2 expression in human gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 989.
Irinotecan (camptothecin-11 (CPT-11)) is an anticancer drug that has been used in the treatment of a wide spectrum of cancer, and irinotecan-containing regimens such as FOLFIRI and FOLFOXIRI are standard chemotherapy regimens for advanced colorectal cancer. Irinotecan is a prodrug that is converted to its active metabolite 7-ethyl-10-hydroxycamptothesin (SN-38) by carboxylesterases CES1 and CES2. CES2 has a far higher hydrolytic efficiency against irinotecan than CES1. Since CES2 expression is higher than other CES isozymes in colon tissue, it might contribute to local (i.e., intratumoral) activation of irinotecan. Recent studies have shown that CES2 expression is regulated by p53 in human colon carcinoma cell lines. TP53 is a tumor suppressor gene and the frequency of its mutations in colorectal cancer is approximately 50%. Therefore, TP53 mutation may cause downregulation of CES2 expression and affect the sensitivity of colorectal cancer to irinotecan. In our previous study, we showed that both CES2 expression and carboxylesterase activity were significantly lower in most colorectal cancer specimens than in adjacent normal tissue. Nevertheless, there was no clear relationship between CES2 expression and TP53 gene status. We also found that p21 expression was significantly reduced in the tumors compared with adjacent normal tissue independently of their TP53 mutational status. Notably, there was a strong positive correlation between p21 and CES2 expression even in the tumors with nonfunctional p53. Recent studies have reported that colorectal tumors developed in proximal colon (right side) and distal colon (left side) exhibit different molecular characteristics and histology. Patients with left-sided colorectal tumors respond well to conventional adjuvant chemotherapies, and the prognosis of these patients is better than that of patients with right-sided colorectal tumors. To test whether location of tumor affects CES2 expression, we compared the CES2 expression levels of tumors that arose from proximal colon with those from distal colon. We also tested the potency and the selectivity of a recently reported CES2 inhibitor. Our results provide important insights into the regulatory mechanism of CES2 expression and its role in colorectal cancer. Citation Format: Momoko Ishimine, Hyeon-Cheol Lee, Hirofumi Nakaoka, Hajime Orita, Toshiyuki Kobayashi, Ituro Inoue, Koichi Sato, Takehiko Yokomizo. Regulatory mechanism of carboxylesterase 2 expression and its role in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5231.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.