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Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells.

Mo L, Pospichalova V, Huang Z, Murphy SK, Payne S, Wang F, Kennedy M, Cianciolo GJ, Bryja V, Pizzo SV, Bachelder RE - PLoS ONE (2015)

Bottom Line: One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells.As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression.Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)].

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.

ABSTRACT
Chemotherapy resistance is the major reason for the failure of ovarian cancer treatment. One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells. As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression. However, whether ascites drives multidrug resistance in ovarian cancer cells awaits elucidation. Here, we demonstrate that when cultured with ascites derived from ovarian cancer-bearing mice, a murine ovarian cancer cell line became less sensitive to paclitaxel, a first line chemotherapeutic agent for ovarian cancer patients. Moreover, incubation of murine ovarian cancer cells in vitro with ascites drives efflux function in these cells. Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)]. To demonstrate relevance of our findings to ovarian cancer patients, we studied relative efflux in human ovarian cancer cells obtained from either patient ascites or from primary tumor. Immortalized cell lines developed from human ascites show increased susceptibility to efflux inhibitors (MRP1, BCRP) compared to a cell line derived from a primary ovarian cancer, suggesting an association between ascites and efflux function in human ovarian cancer. Efflux in ascites-derived human ovarian cancer cells is associated with increased expression of ABC transporters compared to that in primary tumor-derived human ovarian cancer cells. Collectively, our findings identify a novel activity for ascites in promoting ovarian cancer multidrug resistance.

No MeSH data available.


Related in: MedlinePlus

Ascites treatment increases expression of MDR1a/b and BCRP in ID8 cells.Total RNA was harvested from ID8 cells in normal culture as well as from ID8 cells pre-treated with ascites for 7 days. Expression levels of the indicated genes (relative to beta actin) were determined by real-time PCR(A). Fold increases in gene expression (ascites treated ID8 cells over normal ID8 cells) are shown in B. Three independent experiments were performed and error bar represents SD. * indicates p<0.05 and *** p<0.001, Student’s t-test.
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pone.0131579.g003: Ascites treatment increases expression of MDR1a/b and BCRP in ID8 cells.Total RNA was harvested from ID8 cells in normal culture as well as from ID8 cells pre-treated with ascites for 7 days. Expression levels of the indicated genes (relative to beta actin) were determined by real-time PCR(A). Fold increases in gene expression (ascites treated ID8 cells over normal ID8 cells) are shown in B. Three independent experiments were performed and error bar represents SD. * indicates p<0.05 and *** p<0.001, Student’s t-test.

Mentions: We studied the expression of three ABC transporter genes (MDR1, MRP1 and BCRP) that are commonly involved in cancer chemo-resistance. We performed quantitative real-time PCR (q-PCR) on RNA harvested from ID8 cells and ID8 cells pre-treated with ascites. Untreated ID8 cells expressed both MRP1 and BCRP mRNA (Fig 3A). After treatment with ascites in vitro for 7 days, ID8 cells exhibited significantly increased expression of MDR1a (118- fold), MDR1b (75-fold), and BCRP (17-fold)(Fig 3A and 3B).


Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells.

Mo L, Pospichalova V, Huang Z, Murphy SK, Payne S, Wang F, Kennedy M, Cianciolo GJ, Bryja V, Pizzo SV, Bachelder RE - PLoS ONE (2015)

Ascites treatment increases expression of MDR1a/b and BCRP in ID8 cells.Total RNA was harvested from ID8 cells in normal culture as well as from ID8 cells pre-treated with ascites for 7 days. Expression levels of the indicated genes (relative to beta actin) were determined by real-time PCR(A). Fold increases in gene expression (ascites treated ID8 cells over normal ID8 cells) are shown in B. Three independent experiments were performed and error bar represents SD. * indicates p<0.05 and *** p<0.001, Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4493087&req=5

pone.0131579.g003: Ascites treatment increases expression of MDR1a/b and BCRP in ID8 cells.Total RNA was harvested from ID8 cells in normal culture as well as from ID8 cells pre-treated with ascites for 7 days. Expression levels of the indicated genes (relative to beta actin) were determined by real-time PCR(A). Fold increases in gene expression (ascites treated ID8 cells over normal ID8 cells) are shown in B. Three independent experiments were performed and error bar represents SD. * indicates p<0.05 and *** p<0.001, Student’s t-test.
Mentions: We studied the expression of three ABC transporter genes (MDR1, MRP1 and BCRP) that are commonly involved in cancer chemo-resistance. We performed quantitative real-time PCR (q-PCR) on RNA harvested from ID8 cells and ID8 cells pre-treated with ascites. Untreated ID8 cells expressed both MRP1 and BCRP mRNA (Fig 3A). After treatment with ascites in vitro for 7 days, ID8 cells exhibited significantly increased expression of MDR1a (118- fold), MDR1b (75-fold), and BCRP (17-fold)(Fig 3A and 3B).

Bottom Line: One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells.As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression.Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)].

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.

ABSTRACT
Chemotherapy resistance is the major reason for the failure of ovarian cancer treatment. One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells. As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression. However, whether ascites drives multidrug resistance in ovarian cancer cells awaits elucidation. Here, we demonstrate that when cultured with ascites derived from ovarian cancer-bearing mice, a murine ovarian cancer cell line became less sensitive to paclitaxel, a first line chemotherapeutic agent for ovarian cancer patients. Moreover, incubation of murine ovarian cancer cells in vitro with ascites drives efflux function in these cells. Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)]. To demonstrate relevance of our findings to ovarian cancer patients, we studied relative efflux in human ovarian cancer cells obtained from either patient ascites or from primary tumor. Immortalized cell lines developed from human ascites show increased susceptibility to efflux inhibitors (MRP1, BCRP) compared to a cell line derived from a primary ovarian cancer, suggesting an association between ascites and efflux function in human ovarian cancer. Efflux in ascites-derived human ovarian cancer cells is associated with increased expression of ABC transporters compared to that in primary tumor-derived human ovarian cancer cells. Collectively, our findings identify a novel activity for ascites in promoting ovarian cancer multidrug resistance.

No MeSH data available.


Related in: MedlinePlus