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CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K-dependent and FAK-independent fashion.

Johnson EL, Singh R, Johnson-Holiday CM, Grizzle WE, Partridge EE, Lillard JW, Singh S - J Ovarian Res (2010)

Bottom Line: Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death.Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3beta and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion.Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA. shsingh@msm.edu.

ABSTRACT

Background: Cisplatin is more often used to treat ovarian cancer (OvCa), which provides modest survival advantage primarily due to chemo-resistance and up regulated anti-apoptotic machineries in OvCa cells. Therefore, targeting the mechanisms responsible for cisplatin resistance in OvCa cell may improve therapeutic outcomes. We have shown that ovarian cancer cells express CC chemokine receptor-9 (CCR9). Others have also shown that CCL25, the only natural ligand for CCR9, up regulates anti-apoptotic proteins in immature T lymphocytes. Hence, it is plausible that CCR9-mediated cell signals might be involved in OvCa cell survival and inhibition of cisplatin-induced apoptosis. In this study, we investigated the potential role and molecular mechanisms of CCR9-mediated inhibition of cisplatin-induced apoptosis in OvCa cells.

Methods: Cell proliferation, vibrant apoptosis, and TUNEL assays were performed with or without cisplatin treatment in presence or absence of CCL25 to determine the role of the CCR9-CCL25 axis in cisplatin resistance. In situ Fast Activated cell-based ELISA (FACE) assays were performed to determine anti-apoptotic signaling molecules responsible for CCL25-CCR9 mediated survival.

Results: Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death. Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3beta and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion.

Conclusions: Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.

No MeSH data available.


Related in: MedlinePlus

Inhibition of apoptotic signal in cisplatin resistant tumor cells. More than one mechanism is usually observed in resistant cells, and this contributes to the multi-factorial nature of cisplatin resistance. CCR9-dependent anti-apoptotic signalling in OvCa cells involves the PI3K/Akt cascade and phosphorylation of its downstream mediators, GSK-3β and FKHR.
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Figure 6: Inhibition of apoptotic signal in cisplatin resistant tumor cells. More than one mechanism is usually observed in resistant cells, and this contributes to the multi-factorial nature of cisplatin resistance. CCR9-dependent anti-apoptotic signalling in OvCa cells involves the PI3K/Akt cascade and phosphorylation of its downstream mediators, GSK-3β and FKHR.

Mentions: Conflicting studies demonstrated cisplatin activates Akt in several cancer cell lines, which leads to cisplatin resistance [16]. Moreover, it has been shown that cisplatin can transiently induce Akt-mediated phosphorylation of FKHRL1 in the cisplatin-resistant cell line, CAOV-3, with subsequent cytoplasmic retention of FKHRL1 and cell survival [17]. However, cisplatin-treatment alone did not lead to significant increases in phosphorylation of PI3K, Akt, GSK-3β, or FKHR. In fact, cisplatin treatment led to a slight down regulation of Akt activation. However in the presence of CCL25 along with cisplatin, phosphorylation of Akt, GSK-3β and FKHR elevated to significant levels. Taken together, these results suggest that CCL25 treatment contributes to OvCa survival and cisplatin resistance. Moreover, we show that CCR9-dependent anti-apoptotic signalling in OvCa cells involves the PI3K/Akt cascade and phosphorylation of its downstream mediators, GSK-3β and FKHR (Figure 6).


CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K-dependent and FAK-independent fashion.

Johnson EL, Singh R, Johnson-Holiday CM, Grizzle WE, Partridge EE, Lillard JW, Singh S - J Ovarian Res (2010)

Inhibition of apoptotic signal in cisplatin resistant tumor cells. More than one mechanism is usually observed in resistant cells, and this contributes to the multi-factorial nature of cisplatin resistance. CCR9-dependent anti-apoptotic signalling in OvCa cells involves the PI3K/Akt cascade and phosphorylation of its downstream mediators, GSK-3β and FKHR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2914045&req=5

Figure 6: Inhibition of apoptotic signal in cisplatin resistant tumor cells. More than one mechanism is usually observed in resistant cells, and this contributes to the multi-factorial nature of cisplatin resistance. CCR9-dependent anti-apoptotic signalling in OvCa cells involves the PI3K/Akt cascade and phosphorylation of its downstream mediators, GSK-3β and FKHR.
Mentions: Conflicting studies demonstrated cisplatin activates Akt in several cancer cell lines, which leads to cisplatin resistance [16]. Moreover, it has been shown that cisplatin can transiently induce Akt-mediated phosphorylation of FKHRL1 in the cisplatin-resistant cell line, CAOV-3, with subsequent cytoplasmic retention of FKHRL1 and cell survival [17]. However, cisplatin-treatment alone did not lead to significant increases in phosphorylation of PI3K, Akt, GSK-3β, or FKHR. In fact, cisplatin treatment led to a slight down regulation of Akt activation. However in the presence of CCL25 along with cisplatin, phosphorylation of Akt, GSK-3β and FKHR elevated to significant levels. Taken together, these results suggest that CCL25 treatment contributes to OvCa survival and cisplatin resistance. Moreover, we show that CCR9-dependent anti-apoptotic signalling in OvCa cells involves the PI3K/Akt cascade and phosphorylation of its downstream mediators, GSK-3β and FKHR (Figure 6).

Bottom Line: Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death.Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3beta and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion.Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA. shsingh@msm.edu.

ABSTRACT

Background: Cisplatin is more often used to treat ovarian cancer (OvCa), which provides modest survival advantage primarily due to chemo-resistance and up regulated anti-apoptotic machineries in OvCa cells. Therefore, targeting the mechanisms responsible for cisplatin resistance in OvCa cell may improve therapeutic outcomes. We have shown that ovarian cancer cells express CC chemokine receptor-9 (CCR9). Others have also shown that CCL25, the only natural ligand for CCR9, up regulates anti-apoptotic proteins in immature T lymphocytes. Hence, it is plausible that CCR9-mediated cell signals might be involved in OvCa cell survival and inhibition of cisplatin-induced apoptosis. In this study, we investigated the potential role and molecular mechanisms of CCR9-mediated inhibition of cisplatin-induced apoptosis in OvCa cells.

Methods: Cell proliferation, vibrant apoptosis, and TUNEL assays were performed with or without cisplatin treatment in presence or absence of CCL25 to determine the role of the CCR9-CCL25 axis in cisplatin resistance. In situ Fast Activated cell-based ELISA (FACE) assays were performed to determine anti-apoptotic signaling molecules responsible for CCL25-CCR9 mediated survival.

Results: Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death. Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3beta and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion.

Conclusions: Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.

No MeSH data available.


Related in: MedlinePlus