Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors
Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors
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DOI：
10.1093/carcin/bgv012
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发表时间：
2015-04-01
期刊：
影响因子：
4.7
通讯作者：
Shantz, Lisa M.
中科院分区：
文献类型：
--
作者：
Carr, Theresa D.;Feehan, Robert P.;Shantz, Lisa M.
依赖于哺乳动物雷帕霉素靶蛋白（mTOR）的信号转导激活已在多种人类恶性肿瘤中得到证实，我们先前的工作表明mTOR复合物（mTORC）1和mTORC 2可能在皮肤肿瘤发生中发挥独特的作用。这些研究的目的是研究mTORC 2依赖性途径在皮肤肿瘤发展和已建立肿瘤的维持中的功能。使用小鼠，允许空间和时间控制mTORC 2在表皮的条件性敲除其基本成分Rictor，我们研究了mTORC 2损失对表皮增殖和化学致癌作用的影响。结果表明，mTORC 2对于正常表皮增殖和对十四烷酰基佛波醇乙酸酯（TPA）治疗的过度增殖反应都是无效的。与此相反，在DMBA/TPA化学致癌作用开始之前，表皮Rictor的缺失足以显着延迟肿瘤的发展，并导致与对照组相比，肿瘤的数量和大小减少。在荷瘤动物中Rictor表达的沉默引发了已建立的肿瘤的消退，并增加了caspase-3的切割，而没有增殖的变化。体外实验表明，在不存在rictor的情况下，对半胱天冬酶依赖性细胞凋亡的敏感性增加，这依赖于mTORC 2信号传导。这些研究表明，mTORC 2活化是角质形成细胞存活所必需的，并表明mTORC 2的抑制在肿瘤发生的早期阶段通过消除致癌物损伤的细胞而在化学预防中具有价值，并且在通过限制关键的促存活途径而在现有肿瘤的治疗中具有价值。
Activation of signaling dependent on the mammalian target of rapamycin (mTOR) has been demonstrated in a variety of human malignancies, and our previous work suggests that mTOR complex (mTORC) 1 and mTORC2 may play unique roles in skin tumorigenesis. The purpose of these studies was to investigate the function of mTORC2-dependent pathways in skin tumor development and the maintenance of established tumors. Using mice that allow spatial and temporal control of mTORC2 in epidermis by conditional knockout of its essential component Rictor, we studied the effect of mTORC2 loss on both epidermal proliferation and chemical carcinogenesis. The results demonstrate that mTORC2 is dispensable for both normal epidermal proliferation and the hyperproliferative response to treatment with tetradecanoyl phorbol acetate (TPA). In contrast, deletion of epidermal Rictor prior to initiation in DMBA/TPA chemical carcinogenesis was sufficient to dramatically delay tumor development and resulted in reduced tumor number and size compared with control groups. Silencing of Rictor expression in tumor-bearing animals triggered regression of established tumors and increased caspase-3 cleavage without changes in proliferation. In vitro experiments demonstrate an increased sensitivity to caspase-dependent apoptosis in the absence of rictor, which is dependent on mTORC2 signaling. These studies demonstrate that mTORC2 activation is essential for keratinocyte survival, and suggest that inhibition of mTORC2 has value in chemoprevention by eliminating carcinogen-damaged cells during the early stages of tumorigenesis, and in therapy of existing tumors by restricting critical pro-survival pathways.