State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Mol Med. 2011;17(11-12):1262-74. doi: 10.2119/molmed.2011.00176. Epub 2011 Aug 19.
Ovarian cancer is the number one cause of death from gynecologic malignancy. A defective p53 pathway is a hallmark of ovarian carcinoma. The p53 mutation correlates significantly with resistance to platinum-based chemotherapy, early relapse and shortened overall survival in ovarian cancer patients. PUMA (p53 upregulated modulator of apoptosis), a BH3-only Bcl-2 family protein, was recently identified as a transcriptional target of p53 and a potent apoptosis inducer in various cancer cells. In this study, we showed that the induction of PUMA by cisplatin was abolished in p53-deficient SKOV3 cells. Elevated expression of PUMA-induced apoptosis and sensitized A2780s and SKOV3 ovarian cancer cells to cisplatin, and the combination of PUMA and low-dose cisplatin, significantly suppressed xenograft tumor growth in vivo through enhanced induction of apoptosis compared with treatment with PUMA or cisplatin alone. The effects of PUMA were mediated by enhanced caspase activation and release of cytochrome c and Smac (second mitochondria-derived activator of caspase) into the cytosol. Furthermore, PUMA chemosensitized intrinsically resistant SKOV3 cells to cisplatin through downregulation of B-cell lymphoma-extra large (Bcl-x(L)) and myeloid cell leukemia sequence 1 (Mcl-1). PUMA-mediated Bcl-x(L) downregulation mainly happened at the transcription level, whereas PUMA-induced Mcl-1 down-regulation was associated with caspase-dependent cleavage and proteasome-mediated degradation. To our knowledge, these data suggest a new mechanism by which overexpression of PUMA enhances sensitivity of SKOV3 cells to cisplatin by lowering the threshold set simultaneously by Bcl-x(L) and Mcl-1. Taken together, our findings indicate that PUMA is an important modulator of therapeutic responses of ovarian cancer cells and is potentially useful as a chemosensitizer in ovarian cancer therapy.
卵巢癌是妇科恶性肿瘤死亡的首要原因。p53 通路缺陷是卵巢癌的一个标志。p53 突变与铂类化疗耐药、早期复发和卵巢癌患者总生存期缩短密切相关。PUMA（p53 上调凋亡调节剂）是一种 BH3 仅有 Bcl-2 家族蛋白，最近被鉴定为 p53 的转录靶点，也是各种癌细胞中一种有效的凋亡诱导剂。在这项研究中，我们发现顺铂诱导的 PUMA 在 p53 缺陷型 SKOV3 细胞中被消除。PUMA 的高表达诱导凋亡，并使 A2780s 和 SKOV3 卵巢癌细胞对顺铂敏感，与单独使用 PUMA 或顺铂相比，PUMA 与低剂量顺铂联合使用，通过增强凋亡诱导，显著抑制体内异种移植肿瘤生长。PUMA 的作用是通过增强 caspase 激活和细胞色素 c 和 Smac（第二线粒体衍生的半胱天冬酶激活剂）释放到细胞质中来介导的。此外，PUMA 通过下调 B 细胞淋巴瘤-extra large（Bcl-x(L)）和髓系细胞白血病序列 1（Mcl-1）使内在耐药的 SKOV3 细胞对顺铂敏感。PUMA 介导的 Bcl-x(L)下调主要发生在转录水平，而 PUMA 诱导的 Mcl-1 下调与 caspase 依赖性切割和蛋白酶体介导的降解有关。据我们所知，这些数据表明，PUMA 过表达通过降低 Bcl-x(L) 和 Mcl-1 同时设定的阈值，增强 SKOV3 细胞对顺铂的敏感性，这是一种新的机制。总之，我们的研究结果表明，PUMA 是卵巢癌细胞治疗反应的重要调节剂，有望成为卵巢癌治疗的化学增敏剂。
