The Hormel Institute, University of Minnesota, Austin, Minnesota 55912-3679, USA.
Carcinogenesis. 2012 Sep;33(9):1814-21. doi: 10.1093/carcin/bgs234. Epub 2012 Jul 12.
N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide) is a synthetic retinoid that has been tested in clinical trials as a cancer therapeutic and chemopreventive agent. Although 4HPR has been shown to be cytotoxic to many kinds of cancer cells, the underlying molecular mechanisms are only partially understood. Until now, no direct cancer-related molecular target has been reported to be involved in the antitumor activities of 4HPR. Herein, we found that 4HPR inhibited mammalian target of rapamycin (mTOR) kinase activity by directly binding with mTOR, which suppressed the activities of both the mTORC1 and the mTORC2 complexes. The predicted binding mode of 4HPR with mTOR was based on a homology computer model, which showed that 4HPR could bind in the ATP-binding pocket of the mTOR protein through hydrogen bonds and hydrophobic interactions. In vitro studies also showed that 4HPR attenuated mTOR downstream signaling in a panel of non-small-cell lung cancer cells, resulting in growth inhibition. Moreover, knockdown of mTOR in cancer cells decreased their sensitivity to 4HPR. Results of an in vivo study demonstrated that i.p. injection of 4HPR in A549 lung tumor-bearing mice effectively suppressed cancer growth. The expression of mTOR downstream signaling molecules in tumor tissues was also decreased after 4HPR treatment. Taken together, our results are the first to identify mTOR as a direct antitumor target of 4HPR both in vitro and in vivo, providing a valuable rationale for guiding the clinical uses of 4HPR.
N-(4-羟苯基)维 A 酰胺（4HPR，维 A 酸乙酯）是一种合成的维 A 酸衍生物，已在临床试验中作为癌症治疗和化学预防药物进行了测试。尽管已经证明 4HPR 对多种癌细胞具有细胞毒性，但潜在的分子机制尚未完全了解。到目前为止，尚未报道有直接与癌症相关的分子靶标参与 4HPR 的抗肿瘤活性。在此，我们发现 4HPR 通过直接与 mTOR 结合抑制哺乳动物雷帕霉素靶蛋白（mTOR）激酶活性，从而抑制 mTORC1 和 mTORC2 复合物的活性。4HPR 与 mTOR 的预测结合模式基于同源计算机模型，该模型表明 4HPR 可以通过氢键和疏水相互作用结合到 mTOR 蛋白的 ATP 结合口袋中。体外研究还表明，4HPR 减弱了一组非小细胞肺癌细胞中 mTOR 的下游信号转导，导致生长抑制。此外，在癌细胞中敲低 mTOR 会降低其对 4HPR 的敏感性。体内研究结果表明，腹腔注射 4HPR 可有效抑制 A549 肺肿瘤荷瘤小鼠的肿瘤生长。肿瘤组织中 mTOR 下游信号分子的表达也在 4HPR 治疗后下降。总之，我们的研究结果首次确定 mTOR 是 4HPR 在体外和体内的直接抗肿瘤靶标，为指导 4HPR 的临床应用提供了有价值的依据。
