Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib.
Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib.
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DOI：
10.1158/1078-0432.ccr-09-1071
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发表时间：
2009-12-01
期刊：
影响因子：
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通讯作者：
Mitsiades N
中科院分区：
文献类型：
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作者：
Ooi MG;Hayden PJ;Kotoula V;McMillin DW;Charalambous E;Daskalaki E;Raje NS;Munshi NC;Chauhan D;Hideshima T;Buon L;Clynes M;O'Gorman P;Richardson PG;Mitsiades CS;Anderson KC;Mitsiades N
在许多人类恶性肿瘤中，p53通过错义突变或人类MDM2同源物(Hdm2)的过度表达而失活，MDM2是一种泛素化P53的E3泛素连接酶，从而促进其蛋白酶体的降解。在包括多发性骨髓瘤(MM)在内的多种恶性肿瘤中，顺式咪唑啉Nutlin-3可以阻断P53-Hdm2的相互作用，激活P53，诱导细胞凋亡。我们推测，抑制Hdm2介导的P53泛素化可能会增加蛋白酶体抑制引起的P53积聚的后遗症。我们比较了MM细胞和几种上皮性癌症模型对蛋白酶体抑制剂Bortezomib和Nutlin-3联合使用的反应。亚致死浓度的Bortezomib联合Nutlin-3对对Bortezomib敏感的MM细胞株诱导相加的细胞毒作用。然而，重要的是，在乳腺、前列腺、结肠和甲状腺(乳头状癌、滤泡癌、间变性癌和髓样癌)癌细胞系中，这种组合引发了协同细胞毒作用，并增加了p53、p21、hdm2、bax、noxa、PUMA的表达，以及caspase-3和聚ADP核糖聚合酶的裂解。与骨髓基质细胞共培养降低了MM细胞对Nutlin-3单一治疗的敏感性，并与抑制MM细胞中P53活性的证据有关，而Bortezomib-nutlin-3联合治疗即使在存在骨髓基质细胞的情况下也保持了细胞毒性。MM和上皮性癌对Nutlin-3和Bortezomib联合使用的不同反应为揭示P53在Bortezomib诱导的细胞凋亡中的作用提供了新的线索。与Bortezomib同时抑制Hdm2可能会将Bortezomib的应用范围扩大到目前对单药Bortezomib敏感性有限的恶性肿瘤，或在未来扩大到对基于Bortezomib的治疗临床反应降低的MM患者。
p53 is inactivated in many human malignancies through missense mutations or overexpression of the human homologue of Mdm2 (Hdm2), an E3 ubiquitin ligase that ubiquitinates p53, thereby promoting its proteasomal degradation. The cis-imidazoline nutlin-3 can disrupt the p53-Hdm2 interaction and activate p53, inducing apoptosis in vitro in many malignancies, including multiple myeloma (MM). We hypothesized that suppression of Hdm2-mediated p53 ubiquitination may augment sequelae of p53 accumulation caused by proteasomal inhibition. We compared the response of MM cells versus several epithelial cancer models to the proteasome inhibitor bortezomib in combination with nutlin-3. The combination of sublethal concentrations of bortezomib plus nutlin-3 induced additive cytotoxicity against bortezomib-sensitive MM cell lines. Importantly, however, in breast, prostate, colon, and thyroid (papillary, follicular, anaplastic, and medullary) carcinoma cell lines, this combination triggered synergistic cytotoxicity, and increased expression of p53, p21, Hdm2, Bax, Noxa, PUMA, and cleavage of caspase-3 and poly ADP ribose polymerase. Coculture with bone marrow stromal cells attenuated MM cell sensitivity to nutlin-3 monotherapy and was associated with evidence of suppression of p53 activity in MM cells, whereas combined bortezomib-nutlin-3 treatment maintained cytotoxicity even in the presence of bone marrow stromal cells. This differential response of MM versus epithelial carcinomas to combination of nutlin-3 with bortezomib sheds new light on the role of p53 in bortezomib induced apoptosis. Concurrent Hdm2 inhibition with bortezomib may extend the spectrum of bortezomib applications to malignancies with currently limited sensitivity to single-agent bortezomib or, in the future, to MM patients with decreased clinical responsiveness to bortezomib-based therapy.