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PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.

Rincón R, Cristóbal I, Zazo S, Arpí O, Menéndez S, Manso R, Lluch A, Eroles P, Rovira A, Albanell J, García-Foncillas J, Madoz-Gúrpide J, Rojo F - Oncotarget (2015)

Bottom Line: Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation.Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo.Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.

View Article: PubMed Central - PubMed

Affiliation: Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital "Fundación Jiménez Diaz", Madrid, Spain.

ABSTRACT
The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.

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FTY720 impairs cell viability through PP2A activation(A) Treatment with OA inhibits the FTY720-induced PP2A activity in MDA-MB-231 and BT-474 cells. (B) The impaired cell growth induced by FTY720 is restored by the treatment with OA.
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Figure 2: FTY720 impairs cell viability through PP2A activation(A) Treatment with OA inhibits the FTY720-induced PP2A activity in MDA-MB-231 and BT-474 cells. (B) The impaired cell growth induced by FTY720 is restored by the treatment with OA.

Mentions: Furthermore, quantification of PP2A activity by phosphatase assays confirmed that FTY720 led to PP2A activation in both MDA-MB-231 and BT-474 cell lines, observing around 1.5-fold increase in the PP2A activity (Figure 2A). As a control, we pretreated MDA-MB-231 and BT-474 cells with the PP2A inhibitor OA for 90 minutes, followed by incubation with FTY720 or vehicle for 24 hours. OA was used at a concentration that inhibits PP2A but no other phosphatases [24], observing that FTY720-induced PP2A activity was inhibited by OA (Figure 2A). To evaluate whether FTY720 is a specific PP2A activator we quantified PP2A and PP1 activities in MDA-MB-231 and BT-474 cells after FTY720 treatment, observing that FTY720 was able to increase only PP2A activity. To confirm that OA is a specific PP2A inhibitor at this concentration, similar experiments were carried out (Figure S2).


PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.

Rincón R, Cristóbal I, Zazo S, Arpí O, Menéndez S, Manso R, Lluch A, Eroles P, Rovira A, Albanell J, García-Foncillas J, Madoz-Gúrpide J, Rojo F - Oncotarget (2015)

FTY720 impairs cell viability through PP2A activation(A) Treatment with OA inhibits the FTY720-induced PP2A activity in MDA-MB-231 and BT-474 cells. (B) The impaired cell growth induced by FTY720 is restored by the treatment with OA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414191&req=5

Figure 2: FTY720 impairs cell viability through PP2A activation(A) Treatment with OA inhibits the FTY720-induced PP2A activity in MDA-MB-231 and BT-474 cells. (B) The impaired cell growth induced by FTY720 is restored by the treatment with OA.
Mentions: Furthermore, quantification of PP2A activity by phosphatase assays confirmed that FTY720 led to PP2A activation in both MDA-MB-231 and BT-474 cell lines, observing around 1.5-fold increase in the PP2A activity (Figure 2A). As a control, we pretreated MDA-MB-231 and BT-474 cells with the PP2A inhibitor OA for 90 minutes, followed by incubation with FTY720 or vehicle for 24 hours. OA was used at a concentration that inhibits PP2A but no other phosphatases [24], observing that FTY720-induced PP2A activity was inhibited by OA (Figure 2A). To evaluate whether FTY720 is a specific PP2A activator we quantified PP2A and PP1 activities in MDA-MB-231 and BT-474 cells after FTY720 treatment, observing that FTY720 was able to increase only PP2A activity. To confirm that OA is a specific PP2A inhibitor at this concentration, similar experiments were carried out (Figure S2).

Bottom Line: Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation.Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo.Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.

View Article: PubMed Central - PubMed

Affiliation: Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital "Fundación Jiménez Diaz", Madrid, Spain.

ABSTRACT
The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.

Show MeSH
Related in: MedlinePlus