PED Mediates AKT-Dependent Chemoresistance in Human Breast Cancer Cells

Abstract

Killing of tumor cells by cytotoxic therapies, such as chemotherapy or gamma-irradiation, is predominantly mediated by the activation of apoptotic pathways. Refractoriness to anticancer therapy is often due to a failure in the apoptotic pathway. The mechanisms that control the balance between survival and cell death in cancer cells are still largely unknown. Tumor cells have been shown to evade death signals through an increase in the expression of antiapoptotic molecules or loss of proapoptotic factors. We aimed to study the involvement of PED, a molecule with a broad antiapoptotic action, in human breast cancer cell resistance to chemotherapeutic drugs-induced cell death. We show that human breast cancer cells express high levels of PED and that AKT activity regulates PED protein levels. Interestingly, exogenous expression of a dominant-negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy-induced cell death. Thus, AKT-dependent increase of PED expression levels represents a key molecular mechanism for chemoresistance in breast cancer. (Cancer Res 2005; 65(15): 6668-75)

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

“…In tumoral cells including glioma, AKT controls the stability and the antiapoptotic function of the protein PED/PEA-15 by its phosphorylation on ser116. 29,30 We explored the effect of K34c on PED/ PEA-15 expression and phosphorylation in U87MG-α5 high cells. Both were decreased by K34c but not affected by Nutlin3a (Figure 3c).…”

“…Although suspected to be inversely regulated during tumor progression, PEA-15 has been involved in therapy resistances in tumors including glioma. 30,32,[44][45][46] However, no relationship between PEA-15 and the p53 pathway has been described to date. Our data demonstrated that PEA-15 has an impact on p53 stability/activity and is essential to inhibit p53-induced apoptosis.…”

The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway

“…Moreover, the expression of PEA-15 has also been reported in mammary gland and keratinocytes as well as in ovarian and breast cancer (Formisano et al, 2005;Krueger et al, 2005;Stassi et al, 2005;Bartholomeusz et al, 2006). So far, a systematic investigation of PEA-15 expression in astrocytic brain tumors has not been published.…”

“…PEA-15 binds to and sequesters extracellular-regulated kinase (ERK)1/2 in the cytoplasm, thereby preventing its nuclear translocation and the subsequent phosphorylation of nuclear targets (Ramos et al, 2000;Formstecher et al, 2001;Condorelli et al, 2002;Whitehurst et al, 2004;Krueger et al, 2005). The regulation of MAP/ERK-dependent pathways by PEA-15 might also play a role in other biological functions of this protein, which are especially important in cancer cells, such as integrin activation (Ramos et al, 1998;Chou et al, 2003), chemoresistance (Stassi et al, 2005) and migration (Renault-Mihara et al, 2006).…”

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

“…Indeed, PEA-15 is a strong inhibitor of death receptor-dependent apoptosis (Condorelli et al, 1999;Estelles et al, 1999;Kitsberg et al, 1999) but is associated with decreased cell proliferation (Formstecher et al, 2001;Gaumont-Leclerc et al, 2004). Furthermore, a recent study showed that sustained level of PEA-15 participated in Akt-dependent chemoresistance in human breast cancer cells (Stassi et al, 2005). Hence, according to our model of Akt/PEA-15 interaction, we hypothesized that, in some physiopathological context, overexpression of Akt could slow proliferation and render the cells quiescent and resistant to certain forms of apoptosis.…”