Abstract
To overcome cancer cells resistance to pharmacological therapy, the development of new therapeutic approaches becomes urgent. For this purpose, the use of poly(ADP-ribose) polymerase (PARP) inhibitors in combination with other cytotoxic agents could represent an efficacious strategy. Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification that plays a well characterized role in the cellular decisions of life and death. Recent findings indicate that PARP-1 may control the expression of Snail, the master gene of epithelial-mesenchymal transition (EMT). Snail is highly represented in different resistant tumors, functioning as a factor regulating anti-apoptotic programmes. MDA-MB-231 is a Snail-expressing metastatic breast cancer cell line, which exhibits chemoresistance properties when treated with damaging agents. In this study, we show that the PARP inhibitor ABT-888 was capable to modulate the MDA-MB-231 cell response to doxorubicin, leading to an increase in the rate of apoptosis. Our further results indicate that PARP-1 controlled Snail expression at transcriptional level in cells exposed to doxorubicin. Given the increasing interest in the employment of PARP inhibitors as chemotherapeutic adjuvants, our in vitro results suggest that one of the mechanisms through which PARP inhibition can chemosensitize cancer cells in vivo, is targeting Snail expression thus promoting apoptosis.
Highlights
Breast cancer is the most common malignant tumor in women
Recent studies have evidenced that poly(ADPribose) polymerase (PARP) inhibitors may chemosensitize triple negative breast cancer (TNBC) cell lines [53,54,55]
We aim to investigate the possible cross-talk between PARP-1 and Snail in MDA-MB-231 cells, a model of Snail-expressing TNBC cell line, in response to the chemotherapeutic agent doxorubicin
Summary
Despite advances in diagnosis and treatment approaches, the mortality due to breast cancer still remains very high. This is attributable to the fact that cancer cells are able to develop mechanisms of resistance to the therapeutic treatment, a process known as chemoresistance [1, 2]. Snail has been reported to be sufficient to promote mammary tumor recurrence in vivo and high levels of Snail predict decreased relapse-free survival in women with breast cancer [16]. Other studies have shown that Snail confers resistance to cell death induced by lack of survival factors and by pro-apoptotic signals [17] and that Snail downregulation increases cell death in colon tumors in a mouse model [18]. Snail exerts its function through the repression of epithelial genes such as CDH1 (E-cadherin) [19] and through repression of multiple factors with important functions in apoptosis such as TP53, BID, and Caspase-6 [14, 20] or PTEN, a negative effector of the PI3K pathway [21]
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