Khanna Anchit, Rane Jayant K, Kivinummi Kati K, Urbanucci Alfonso, Helenius Merja A, Tolonen Teemu T, Saramäki Outi R, Latonen Leena, Manni Visa, Pimanda John E, Maitland Norman J, Westermarck Jukka, Visakorpi Tapio
Prostate Cancer Research Center (PCRC), Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, Tampere, Finland.
Adult Cancer Program, The Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW Medicine, University of New South Wales, Sydney, Australia.
Oncotarget. 2015 Aug 14;6(23):19661-70. doi: 10.18632/oncotarget.3875.
Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients . CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired.These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer.
残余雄激素受体（AR）信号传导以及癌症干细胞样细胞（SCs）的存在是临床上具有挑战性的去势抵抗性前列腺癌（CRPC）的两个新出现的范例。因此，鉴定在癌症干细胞群体中也过表达的AR靶蛋白将是一种有吸引力的治疗方法。我们对三百多个临床样本和患者来源的前列腺上皮培养物（PPECs）的分析表明，蛋白磷酸酶2A癌性抑制剂（CIP2A）就是这样一个靶点。CIP2A在激素初治前列腺癌（HN-PC）和CRPC患者中均显著过表达。CIP2A在HN-PC和CRPC干细胞中也分别过表达3倍和30倍。还证明了AR在体内与CIP2A内含子区域的结合及其在AR中度和AR高表达LNCaP细胞模型系统中的功能。此外，我们表明AR在mRNA和蛋白质水平上均正向调节CIP2A的表达。最后，CIP2A的缺失降低了AR非依赖性PPECs以及AR反应性LNCaP细胞的细胞活力和集落形成效率，其中非锚定依赖性生长也受到损害。这些发现确定CIP2A是AR信号传导和癌症干细胞功能的共同特征，突出了其在临床上最具挑战性的前列腺病理：去势抵抗性前列腺癌中的潜在治疗意义。
