Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor
Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor
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DOI：
10.1073/pnas.0400835101
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发表时间：
2004-04-06
影响因子：
11.1
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
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作者：
Sodhi, A;Montaner, S;Gutkind, JS
我们最近设计了一种体内内皮细胞特异性逆转录病毒基因转移系统，并发现一个单一的卡波西肉瘤（KS）相关疱疹病毒/人类疱疹病毒8基因编码的G蛋白偶联受体（vGPCR），足以诱导KS样肿瘤小鼠。通过使用这个系统，我们在这里显示Akt信号通路在vGPCR肿瘤发生中起着核心作用。事实上，组成型活性Akt足以诱导小鼠的良性血管瘤，而PTEN（10号染色体上缺失的磷酸酶和张力同源物）的杂合子性适度增强基础Akt活性，显著增强vGPCR肉瘤形成。对来自AIDS患者的KS活检的检查显示，活性Akt是一个突出的特征，支持Akt在人类卡波西肉瘤发生中的作用。通过使用vGPCR激动剂依赖性突变体，我们进一步建立了组成型活性作为vGPCR肉瘤发生的要求，验证了靶向抑制关键vGPCR信号通路作为预防其致癌潜力的方法。这些观察结果促使我们探索抑制Akt活化作为KS治疗的分子方法的功效。药理学抑制Akt途径与化疗剂7-羟基-星形孢菌素防止增殖的vGPCR表达内皮细胞在体外和抑制其在体内的致瘤潜力。两者都与Akt活性降低有关。这些结果确定Akt作为vGPCR肉瘤发生中的重要参与者，并证明了靶向该途径的药物在治疗KS中的治疗潜力。
We have recently engineered an in vivo endothelial cell-specific retroviral gene transfer system and found that a single Kaposi's sarcoma (KS)-associated herpesvirus/human herpesvirus 8 gene encoding a G protein-coupled receptor (vGPCR), is sufficient to induce KS-like tumors in mice. By using this system, we show here that the Akt signaling pathway plays a central role in vGPCR oncogenesis. Indeed, a constitutively active Akt was sufficient to induce benign hemangiomas in mice, whereas heterozyogosity for PTEN (the phosphatase and tension homologue deleted on chromosome 10), modestly enhancing basal Akt activity, dramatically enhanced vGPCR sarcomagenesis. Examination of KS biopsies from AIDS patients revealed active Akt as a prominent feature, supportive of a role for Akt in human Kaposi's sarcomagenesis. By using a vGPCR agonist-dependent mutant, we further establish constitutive activity as a requirement for vGPCR sarcomagenesis, validating targeted inhibition of key vGPCR signaling pathways as an approach for preventing its oncogenic potential. These observations prompted us to explore the efficacy of inhibiting Akt activation as a molecular approach to KS treatment. Pharmacological inhibition of the Akt pathway with the chemotherapeutic agent 7-hydroxy-staurosporine prevented proliferation of vGPCR-expressing endothelial cells in vitro and inhibited their tumorigenic potential in vivo. Both were associated with a decrease in Akt activity. These results identify Akt as an essential player in vGPCR sarcomagenesis and demonstrate the therapeutic potential of drugs targeting this pathway in the treatment of KS.