Dual roles of PARP-1 promote cancer growth and progression.
Dual roles of PARP-1 promote cancer growth and progression.
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DOI：
10.1158/2159-8290.cd-12-0120
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发表时间：
2012-12
期刊：
影响因子：
28.2
通讯作者：
Knudsen KE
中科院分区：
文献类型：
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作者：
Schiewer MJ;Goodwin JF;Han S;Brenner JC;Augello MA;Dean JL;Liu F;Planck JL;Ravindranathan P;Chinnaiyan AM;McCue P;Gomella LG;Raj GV;Dicker AP;Brody JR;Pascal JM;Centenera MM;Butler LM;Tilley WD;Feng FY;Knudsen KE
聚ADP-核糖聚合酶-1（PARP-1）是一种丰富的核酶，其通过聚ADP-核糖的酰化修饰底物。PARP-1在DNA损伤修复中具有良好的功能，并且还作为转录因子的环境特异性调节剂发挥作用。使用多种模型，数据表明，在存在和不存在遗传毒性损伤的情况下，PARP-1在雄激素受体（AR）阳性前列腺癌（PCa）细胞中增强促肿瘤发生作用。在机制上，PARP-1被募集到AR功能位点，从而促进AR占据和AR功能。在遗传学定义的系统中进一步证实，PARP-1支持AR转录功能，并且在晚期PCa模型中，PARP-1酶活性增强，进一步将PARP-1与AR活性和疾病进展联系起来。体内分析表明，PARP-1活性是异种移植肿瘤中AR功能以及体内肿瘤细胞生长和去势抵抗的产生和维持所必需的。最后，在原发性人类肿瘤的新型外植体系统中，靶向PARP-1有效抑制肿瘤细胞增殖。总的来说，这些研究确定了PARP-1在促进疾病进展方面的新功能，并最终表明PARP-1的双重功能可以靶向人PCa，以抑制肿瘤生长和进展为去势抵抗。
Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that modifies substrates by poly(ADP-ribose)-ylation. PARP-1 has well-described functions in DNA damage repair, and also functions as a context-specific regulator of transcription factors. Using multiple models, data demonstrate that PARP-1 elicits pro-tumorigenic effects in androgen receptor (AR)-positive prostate cancer (PCa) cells, both in the presence and absence of genotoxic insult. Mechanistically, PARP-1 is recruited to sites of AR function, therein promoting AR occupancy and AR function. It was further confirmed in genetically-defined systems that PARP-1 supports AR transcriptional function, and that in models of advanced PCa, PARP-1 enzymatic activity is enhanced, further linking PARP-1 to AR activity and disease progression. In vivo analyses demonstrate that PARP-1 activity is required for AR function in xenograft tumors, as well as tumor cell growth in vivo and generation and maintenance of castration-resistance. Finally, in a novel explant system of primary human tumors, targeting PARP-1 potently suppresses tumor cell proliferation. Collectively, these studies identify novel functions of PARP-1 in promoting disease progression, and ultimately suggest that the dual functions of PARP-1 can be targeted in human PCa to suppress tumor growth and progression to castration-resistance.