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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.

SUBMITTER: Koh I

PROVIDER: S-EPMC4944882 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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

Koh Iemasa I Hinoi Takao T Sentani Kazuhiro K Hirata Eiji E Nosaka Suguru S Niitsu Hiroaki H Miguchi Masashi M Adachi Tomohiro T Yasui Wataru W Ohdan Hideki H Kudo Yoshiki Y

Cancer medicine 20160406 7

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 can ...[more]

PMID: 27060927

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Project description:Background:Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux metabolites and xenobiotics. They are highly conserved in sequence and function in bacteria and eukaryotes and play important roles in cellular homeostasis, as well as in avoidance of antibiotics and cancer therapies. Recent evidence also documents a critical role in reproductive health and in protecting the ovary from environmental toxicant effects. The most well understood MDRs are MDR-1 (P-glycoprotein (P-gp) also known as ABCB1) and BCRP (breast cancer resistance protein) and are both expressed in the ovary. We have previously shown that MDR-1 mRNA steady state expression changes throughout the murine estrous cycle, but expression appears to increase in association with the surge in estradiol during proestrus. Methods:Here we test the model that MDR-1 and BCRP are regulated by estrogen, the major hormonal product of the ovary. This was performed by administering 6-week-old female mice either sesame oil (vehicle control) or oral ethinyl estradiol at 1 ?g, 10 ?g, and 100 ?g or PROGESTERONE at 0.25mg, 0.5 mg or 1 mg or a combination of both for 5 days. The mice were then sacrificed, and the ovaries were removed and cleaned. Ovaries were used for qPCR, immunoblotting, and immnunolabeling. Results:We found that oral ethinyl estradiol did not influence the steady state mRNA of MDR-1 or BCRP. Remarkably, the effect on mRNA levels neither increased or decreased in abundance upon estrogen exposures. Conversely, we observed less MDR-1 protein expression in the groups treated with 1 ?g and 10 ?g, but not 100 ?g of ethinyl estradiol compared to controls. MDR-1 and BCRP are both expressed in pre-ovulatory follicles. When we tested progesterone, we found that MDR-1 mRNA increased at the dosages of 0.25 mg and 0.5 mg, but protein expression levels were not statistically significant. Combined oral ethinyl estradiol and progesterone significantly lowered both MDR-1 mRNA and protein. Conclusions:Progesterone appears to influence MDR-1 transcript levels, or steady state levels. This could have implications for better understanding how MDR-1 can be modulated during times of toxic exposure. Understanding the normal physiology of MDR-1 in the ovary will expand the current knowledge in cancer biology and reproduction.

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Dataset Information

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

Publications

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

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