Mariano Germano, Ricciardi Maria Rosaria, Trisciuoglio Daniela, Zampieri Michele, Ciccarone Fabio, Guastafierro Tiziana, Calabrese Roberta, Valentini Elisabetta, Tafuri Agostino, Del Bufalo Donatella, Caiafa Paola, Reale Anna
Department of Cellular Biotechnologies and Haematology, "Sapienza" University of Rome, Italy.
Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Oncotarget. 2015 Jun 20;6(17):15008-21. doi: 10.18632/oncotarget.3634.
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.
为克服癌细胞对药物治疗的抗性，开发新的治疗方法变得刻不容缓。为此，使用聚（ADP - 核糖）聚合酶（PARP）抑制剂与其他细胞毒性药物联合使用可能是一种有效的策略。聚（ADP - 核糖基）化（PARylation）是一种翻译后修饰，在细胞生死决策中发挥着明确的作用。最近的研究结果表明，PARP - 1可能控制上皮 - 间质转化（EMT）的主控基因Snail的表达。Snail在不同的耐药肿瘤中高度表达，作为调节抗凋亡程序的因子发挥作用。MDA - MB - 231是一种表达Snail的转移性乳腺癌细胞系，在用损伤剂处理时表现出化学抗性。在本研究中，我们表明PARP抑制剂ABT - 888能够调节MDA - MB - 231细胞对阿霉素的反应，导致凋亡率增加。我们的进一步结果表明，PARP - 1在暴露于阿霉素的细胞中在转录水平上控制Snail的表达。鉴于对使用PARP抑制剂作为化疗佐剂的兴趣日益增加，我们的体外结果表明，PARP抑制在体内使癌细胞化学增敏的机制之一是靶向Snail表达从而促进凋亡。
