The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis.
The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis.
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DOI：
10.18632/oncotarget.2229
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发表时间：
2014-08-30
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Luk SU;Xue H;Cheng H;Lin D;Gout PW;Fazli L;Collins CC;Gleave ME;Wang Y
治疗耐药性是晚期前列腺癌治疗的主要挑战，部分是基于对细胞凋亡的耐药性。细胞凋亡抑制剂（IAP）蛋白家族被认为通过抑制细胞凋亡在癌症存活和耐药中发挥关键作用。在IAP家族成员中，已知cIAP1、cIAP2、XIAP和survivin在前列腺癌中上调。BIRC6是一种研究较少的IAP成员，最近被证明在去势抵抗性前列腺癌（CRPC）中升高。在本研究中，我们发现了临床前列腺癌标本中BIRC6表达升高与患者预后不良因素之间的相关性，以及某些IAP成员的共同上调。鉴于此，我们设计了反义寡核苷酸，同时靶向BIRC6和另一个共同上调的IAP成员（dASOs）。两个以BIRC6+cIAP1和BIRC6+survivin为靶点的dASOs对CRPC细胞增殖的抑制作用显著高于单一BIRC6靶点。生长抑制与细胞凋亡增加、细胞周期阻滞和NFkB活化抑制有关。此外，用任何一种dASO治疗都会导致体内活肿瘤体积显著降低，没有主要的宿主毒性。本研究表明，基于birc6的双iap靶向ASOs是治疗晚期前列腺癌的潜在新型药物。
Treatment resistance, the major challenge in the management of advanced prostate cancer, is in part based on resistance to apoptosis. The Inhibitor of Apoptosis (IAP) protein family is thought to play key roles in survival and drug resistance of cancer via inhibition of apoptosis. Of the IAP family members, cIAP1, cIAP2, XIAP and survivin are known to be up-regulated in prostate cancer. BIRC6, a much less studied IAP member, was recently shown to be elevated in castration-resistant prostate cancer (CRPC). In the present study, we showed a correlation between elevated BIRC6 expression in clinical prostate cancer specimens and poor patient prognostic factors, as well as co-upregulation of certain IAP members. In view of this, we designed antisense oligonucleotides that simultaneously target BIRC6 and another co-upregulated IAP member (dASOs). Two dASOs, targeting BIRC6+cIAP1 and BIRC6+survivin, showed substantial inhibition of CRPC cell proliferation, exceeding that obtained with single BIRC6 targeting. The growth inhibition was associated with increased apoptosis, cell cycle arrest and suppression of NFkB activation. Moreover, treatment with either dASO led to significantly lower viable tumor volume in vivo, without major host toxicity. This study shows that BIRC6-based dual IAP-targeting ASOs represent potential novel therapeutic agents against advanced prostate cancer.
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影响因子：
3.7
作者：
Hensley P;Mishra M;Kyprianou N
通讯作者：
Kyprianou N
影响因子：
82.9
作者：
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16
作者：
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DOI：
10.1006/bbrc.1999.1585
发表时间：
1999-11-02
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
5.1
作者：
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