The p53-mediated sensitivity of cancer cells to chemotherapeutic agents is conditioned by the status of the retinoblastoma protein
The p53-mediated sensitivity of cancer cells to chemotherapeutic agents is conditioned by the status of the retinoblastoma protein
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DOI：
10.1002/path.2612
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发表时间：
2009-11-01
影响因子：
7.3
通讯作者：
Trere, Davide
中科院分区：
文献类型：
--
作者：
Derenzini, Massimo;Brighenti, Elisa;Trere, Davide
尽管在细胞抑制剂/细胞毒性应激下，p53在决定细胞周期阻滞和/或细胞凋亡中的作用已经得到证实，但在人类癌症中，p53状态在化疗药物应答中的作用尚未明确定义。我们想知道这是否是因为p53对化疗药物的介导反应可能受到视网膜母细胞瘤蛋白（pRb）状态的制约，pRb是p53稳定激活的途径的下游因子，在癌症中经常被破坏。p53介导的化疗敏感性对pRb状态的依赖性在一项前瞻性研究中首次被研究，该研究旨在探讨p53在辅助化疗（5-氟尿嘧啶、甲氨蝶呤和环磷酰胺）治疗的乳腺癌患者中的预后相关性。无病生存期（DFS）的单因素分析表明，免疫组织化学评估的p53状态，如果独立考虑pRb状态，则没有预测价值。然而，在pRb既没有丢失也没有过度磷酸化的癌症患者中，p53与预后显著相关，在DFS的多变量分析（包括已建立的临床和组织病理学预后参数）中，p53被发现是预测疾病进展的唯一因素。然后，我们研究了pRb状态在p53介导的对5-氟尿嘧啶和甲氨蝶呤或阿霉素治疗的三种人类癌细胞系的反应中的作用。我们发现在这些细胞中，化学敏感性严格依赖于p53状态。然而，RB1沉默或p16（INK4 α）沉默引起的pRb过度磷酸化，都强烈降低了p53介导的对化疗药物的反应。这些结果表明：(a) p53介导的对化疗药物的反应仅在pRb通路未改变的癌症中诱导细胞抑制剂/细胞毒性作用；(b) p53状态实际上可以预测这组癌症患者的临床结果。版权所有(C) 2009大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
Despite the well-established function of p53 in determining cell cycle arrest and/or apoptosis in response to cytostatic/cytotoxic stresses, the role of the p53 status in the response to chemotherapeutic agents in human cancers has been not clearly defined. We wondered whether this was due to the fact that the p53-mediated response to chemotherapy drugs might be conditioned by the status of the retinoblastoma protein (pRb), a downstream factor of the pathway activated by p53 stabilization, which is frequently disrupted in cancer. The dependence of p53-mediated chemosensitivity on pRb status was first investigated in a prospective study on the prognostic relevance of p53 in breast cancer patients treated with adjuvant chemotherapy (5-fluorouracil, methotrexate and cyclophosphamide). Univariate analysis of disease-free survival (DFS) indicated that the p53 status, immunohistochemically evaluated, had no predictive value if considered independently of the pRb status. However, in patients with cancer with pRb neither lost nor hyperphosphorylated, p53 was significantly associated with the prognosis and, in a multivariate analysis of DFS including the established clinical and histopathological prognostic parameters, was found to be the only factor predicting the progression of the disease. We then studied the role of pRb status in the p53-mediated response to 5-fluorouracil and methotrexate or doxorubicin treatment in three human cancer cell lines. We found that in these cells the chemosensitivity was strictly dependent on the p53 status. However, either RB1 silencing or pRb hyperphosphorylation, caused by, p16(INK4 alpha) silencing, strongly reduced the p53-mediated response to chemotherapeutic agents. These results demonstrated that: (a) the p53-mediated response to chemotherapeutic agents induces a cytostatic/cytotoxic effect only in cancers with unaltered pRb pathway; and (b) the p53 status can actually predict the clinical outcome in this group of cancer patients. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.