Rapamycin is a potent inhibitor of skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.
Rapamycin is a potent inhibitor of skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.
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DOI：
10.1158/1940-6207.capr-10-0375
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
DiGiovanni J
中科院分区：
文献类型：
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作者：
Checkley LA;Rho O;Moore T;Hursting S;DiGiovanni J
PI3K/Akt信号的异常激活与多种人类癌症的发生和进展有关。在用佛波酯TPA处理诱发皮肤肿瘤的过程中，表皮Akt的活化以及Akt的几种下游效应物，包括mTORC1的活化都发生了。Rapamycin是一种已建立的mTORC1抑制剂，我们利用Rapamycin进一步探索mTORC1信号在上皮癌变中的作用，特别是在肿瘤促进阶段。雷帕霉素阻断了tpa诱导的mTORC1以及几个下游靶点的激活。此外，外用雷帕霉素治疗tpa诱导的表皮增生和增生呈剂量依赖性。在这个多重处理实验中，对小鼠皮肤的免疫组织化学分析显示，雷帕霉素还显著减少了TPA处理后真皮中浸润的巨噬细胞、t细胞、中性粒细胞和肥大细胞的数量。在以DMBA为引发剂，TPA为启动剂的两阶段皮肤癌变方案中，雷帕霉素（TPA前30分钟局部给予5-200 nmol /小鼠）具有强大的抗促进作用，可降低肿瘤发生率和肿瘤多样性。此外，局部应用雷帕霉素治疗现有乳头瘤可诱导肿瘤消退和/或抑制进一步生长。总的来说，这些数据表明雷帕霉素是一种有效的皮肤肿瘤促进抑制剂，并表明通过mTORC1的信号传导在皮肤肿瘤促进过程中起着重要作用。数据还表明，单独阻断该途径或与靶向其他途径的其他药物联合可能是预防上皮癌变的有效策略。
Aberrant activation of PI3K/Akt signaling has been implicated in the development and progression of multiple human cancers. During the process of skin tumor promotion induced by treatment with the phorbol ester TPA, activation of epidermal Akt occurs as well as several downstream effectors of Akt, including the activation of mTORC1. Rapamycin, an established mTORC1 inhibitor, was used to further explore the role of mTORC1 signaling in epithelial carcinogenesis, specifically during the tumor promotion stage. Rapamycin blocked TPA-induced activation of mTORC1 as well as several downstream targets. In addition, TPA-induced epidermal hyperproliferation and hyperplasia were inhibited in a dose-dependent manner with topical rapamycin treatments. Immunohistochemical analyses of the skin from mice in this multiple treatment experiment revealed that rapamycin also significantly decreased the number of infiltrating macrophages, T-cells, neutrophils, and mast cells seen in the dermis following TPA treatment. Using a two-stage skin carcinogenesis protocol with DMBA as initiator and TPA as the promoter, rapamycin (5–200 nmol per mouse given topically 30 minutes prior to TPA) exerted a powerful anti-promoting effect, reducing both tumor incidence and tumor multiplicity. Moreover, topical application of rapamycin to existing papillomas induced regression and/or inhibited further growth. Overall, the data indicate that rapamycin is a potent inhibitor of skin tumor promotion and suggest that signaling through mTORC1 contributes significantly to the process of skin tumor promotion. The data also suggest that blocking this pathway either alone or in combination with other agents targeting additional pathways may be an effective strategy for prevention of epithelial carcinogenesis.