Identification of mammalian target of rapamycin as a direct target of fenretinide both in vitro and in vivo

Hua Xie, Feng Zhu, Zunnan Huang, Mee Hyun Lee, Dong Joon Kim, Xiang Li, Do Young Lim, Sung Keun Jung, Soouk Kang, Haitao Li, Kanamata Reddy, Lei Wang, Weiya Ma, Ronald A. Lubet, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1814-1821
Number of pages8
JournalCarcinogenesis
Volume33
Issue number9
DOIs
StatePublished - Sep 2012

Bibliographical note

Funding Information:
The Hormel Foundation and National Institutes of Health (CA027502, CA120388, R37 CA081064 and ES016548) and NCI Contract Number HHSN-261200533001C-NO1-CN-53301 and N01-CN-43309-18018-01WA 13B.

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