Downregulation of Epidermal Growth Factor Receptor Expression Contributes toα-TEA's Proapoptotic Effects in Human Ovarian Cancer Cell Lines

Ming-Chieh Shun,Bob G Sanders,Sook-Kyung Park,Kimberly Kline,Weiping Yu

doi:10.1155/2010/824571

Abstract

RRR-α-tocopherol derivative α-TEA (RRR-α-tocopherol ether-linked acetic acid analog) has been shown to be a potent antitumor agent both in vivo and in vitro. In this study, we investigated the effects of α-TEA on the expression of epidermal growth factor receptor (EGFR) family members, ErbB1, 2 and 3, and the role of ErbB 2 and 3 in α-TEA-induced apoptosis and suppression of Akt, FLIP and survivin in the cisplatin-sensitive (A2780S) and -resistant (A2780/CP70R) human ovarian cancer cell lines. Data show that α-TEA's ability to induced apoptosis was associated with reduced expression of ErbB1 (cisplatin-resistant cells), 2 and 3 (both cell types) and reduced levels of the phosphorylated (active) form of Akt; as well as, reduced levels of FLIP and survivin proteins in both cell types. Ectopic overexpression and siRNA knockdown studies showed that ErbB2, ErbB3, Akt, FLIP and survivin are involved in α-TEA-induce apoptosis and that α-TEA downregulates FLIP and survivin via suppression of pAkt, which is mediated by ErbB2 and ErB3. Thus, α-TEA is a potent pro-apoptotic agent for both cisplatin-sensitive and -resistant ovarian cancer cell lines in cell culture and it produces cell death, at least in part, by downregulation of members of the EGFR family.

Highlights

Ovarian cancer ranks eighth among all cancers in women in terms of estimated new cases and fifth in estimated deaths [1]
We investigated the effect of α-TEA on the expression of epidermal growth factor receptor (EGFR) family proteins and studied the roles of ErbB2 and ErbB3 in α-TEA-induced apoptosis and suppression of Akt, FLIP and survivin antiapoptotic/prosurvival factors
Data in this paper showed the following: (i) α-TEA is an effective stand alone anticancer agent for human ovarian cancer cell lines in that it inhibits both cisplatin-sensitive and -resistant ovarian cancer cells growth in culture by both decreasing cell proliferation and inducing apoptosis. (ii) The downregulation of ErbB2 and ErbB3/Akt/FLIP and survivin signaling events is necessary for α-TEA-induced apoptosis, and (iii) ErbB1 is highly expressed in the A2780/CP70R cells and below levels of detection in the A2780S cells, suggesting that ErbB1 may play a role in cisplatin resistance

Summary

Introduction

Ovarian cancer ranks eighth among all cancers in women in terms of estimated new cases and fifth in estimated deaths [1]. A majority of patients with ovarian cancer require treatment with cytotoxic chemotherapy. Cisplatin or carboplatin, are the most effective firstline treatments; despite initial promising responses, a high percentage of cases develop chemoresistance which significantly hinders successful treatment outcomes [2, 3]. There is a great need to develop agents for treatment of drug resistant ovarian tumors. The epidermal growth factor receptor (EGFR) family (ErbB family) of type I receptor tyrosine kinases (RTKs) has four members: EGFR/ErbB1, ErbB2, ErbB3, and ErbB4 ( referred to as HER1, HER2, HER3 and HER4).

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