Abstract
Prion protein (PrP) is well studied for its pathogenic role in prion disease, but its potential contribution to other pathological processes is less understood. PrP is expressed in a variety of cancers and at least in pancreatic and breast cancers, its expression appears to be associated with poor prognosis. To understand the role of PrP in breast cancer cells, we knocked down PrP expression in MDA-MB-435 breast cancer cells with small interfering RNA and subjected these cells to a series of analyses. We found that PrP knockdown in these cells does not affect cell proliferation or colony formation, but significantly influences the cellular response to cytotoxic stimuli. Compared to control cells, PrP knockdown cells exhibited an increased susceptibility to serum deprivation induced apoptosis, no change to staurosporine- or paclitaxel-induced cell deaths, and a reduced susceptibility to chemotherapy drug doxorubicin-induced cell death. To understand the mechanism of unexpected role of PrP in exacerbating doxorubicin-induced cytotoxicity, we analyzed cell death related Bcl-2 family proteins. We found that PrP knockdown alters the expression of several Bcl-2 family proteins, correlating with increased resistance to doxorubicin-induced cytotoxicity. Moreover, the enhanced doxorubicin resistance is independent of DNA damage related p53 pathway, but at least partially through the ERK1/2 pathway. Together, our study revealed that silencing PrP in MDA-MB-435 breast cancer cells results in very different responses to various cytotoxic stimuli and ERK1/2 signaling pathway is involved in PrP silencing caused resistance to doxorubicin.
Highlights
Prion protein (PrP) is a glycosylphosphatidylinositol (GPI)anchored cell surface glycoprotein, which is widely expressed in various tissues with most abundant expression in the central nervous system
Previous studies of PrP in breast cancer are generally consistent with the notion that PrP expression increases the resistance to cytotoxicity [11,15,16,17,18], indicating that reducing PrP expression could potentially enhance the efficiency of chemotherapy
Our study intended to test whether PrP knockdown is able to enhance chemotherapeutic drug induced toxicity in breast cancer cells without pre-selection
Summary
Prion protein (PrP) is a glycosylphosphatidylinositol (GPI)anchored cell surface glycoprotein, which is widely expressed in various tissues with most abundant expression in the central nervous system. Besides its role in prion disease, normal PrP expression has been found to contribute to many important biological processes, such as cell adhesion, neurite outgrowth, synaptic transmission, oxidative stress, cell survival, etc [5,6,7]. Various cellular mechanisms have been proposed to explain the role of PrP in cancer cells, including the activation of PI3K/Akt signaling pathway to up-regulate cyclin D in gastric cancer cells [9], chemotherapy drug induced PrP interaction with P-glycoprotein (P-gp, ATP-dependent drug-efflux pumps ABCB1) in a drugresistant MCF7 breast cancer subline [15], and the presence of an aberrantly processed pro-PrP form that disrupts normal cell physiology by binding to filamin A in melanoma and pancreatic cancer cells [12,13]
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