Regulation of multidrug resistance 1 expression by CDX2 in ovarian mucinous adenocarcinoma.

Abstract

Epithelial ovarian cancer is an aggressive gynecological malignancy with a high mortality rate. Resistance against chemotherapeutic agents often develops in ovarian cancer patients, contributing to high recurrence rates. The multidrug resistance 1 (MDR1/ABCB1) gene encodes P-glycoprotein, which affects the pharmacokinetic properties of anticancer agents. We previously reported that the Caudal-related homeobox transcription factor CDX2 transcriptionally regulates MDR1 expression in colorectal cancer. CDX2 is a factor that influences cancer cell differentiation, malignancy, and cancer progression. We hypothesized that profiling of CDX2 and MDR1 expression could be an effective strategy for predicting anticancer drug resistance. We studied the expression of these factors in clinical samples from ovarian cancer patients. We found that endogenous MDR1 expression was positively associated with CDX2 expression in ovarian mucinous adenocarcinoma. Using ovarian mucinous adenocarcinoma cell lines, we also observed decreased MDR1 expression following inhibition of CDX2 by RNA interference. In addition, CDX2 overexpression in MN-1 cells, which display low endogenous CDX2, resulted in upregulation of MDR1 expression. CDX2 induced MDR1-dependent resistance to vincristine and paclitaxel, which was reversed by treatment with the MDR1-specific inhibitor verapamil. Our findings show that CDX2 promotes upregulation of MDR1 expression, leading to drug resistance in ovarian mucinous adenocarcinoma. Therefore, our study demonstrates the potential of novel chemotherapy regimens based on CDX2 status and MDR1 expression in ovarian mucinous adenocarcinoma.

• Authors: Iemasa Koh, Takao Hinoi, Kazuhiro Sentani, Eiji Hirata, Suguru Nosaka, Hiroaki Niitsu, Masashi Miguchi, Tomohiro Adachi, Wataru Yasui, Hideki Ohdan, Yoshiki Kudo
• Journal: Cancer medicine (Cancer Med) Vol. 5 Issue 7 Pg. 1546-55 (07 2016) ISSN: 2045-7634 [Electronic] United States
• PMID: 27060927 (Publication Type: Journal Article)
• Copyright: © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• CDX2 Transcription Factor

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Adenocarcinoma, Mucinous (genetics, metabolism, pathology)
• Antineoplastic Agents (pharmacology)
• CDX2 Transcription Factor (genetics, metabolism)
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms, Glandular and Epithelial (genetics, metabolism, pathology)
• Ovarian Neoplasms (genetics, metabolism, pathology)
• RNA Interference