Rapamycin: An anti-cancer immunosuppressant?
Introduction
Rapamycin is perhaps best known as a potent immunosuppressive agent. It is unclear from this vantage point what utility rapamycin might have as an anti-cancer agent. This perspective however stems from the historical development of rapamycin use rather than the intrinsic nature of rapamycin action. The aim of this review is to rationalize how rapamycin is able to act both as an immunosuppressive agent and an anti-cancer agent.
Rapamycin was first identified as an anti-fungal agent produced by the bacterium Streptomyces hygroscopicus [1], [2] and was subsequently demonstrated to be a potent immunosuppressive agent [3], [4], [5], [6]. The target of rapamycin (TOR) was identified in a screen of yeast mutants able to proliferate in the presence of rapamycin [7]. A mammalian protein homologous to TOR (mTOR) was isolated later based on its ability to bind the FK506 binding protein FKBP12 [8], [9], [10]. TOR bound to FKBP12 in the presence of rapamycin, but not in the presence of the related immunosuppressant bacterial macrolide FK506. mTOR is a 289 kDa protein that is evolutionarily related to lipid kinases, but exhibits protein serine/threonine kinase activity (reviewed in [11]).
Section snippets
TOR and mTOR regulate cell proliferation in response to nutrient availability
Cell proliferation must be regulated such that cell division occurs only when adequate levels of all necessary nutrients are available. However, despite detailed knowledge of how cells respond to growth factors, relatively little is known concerning how cells respond to changes in nutrient levels. In budding yeast, the TOR proteins mediate responses to levels of nutrients such as nitrogen [12], [13]. In mammals, mTOR integrates signals and mediates biological responses to growth factors and
Rapamycin as an immunosuppressant
Shortly after it was first described as an anti-fungal antibiotic [1], [2] rapamycin was demonstrated to have immunosuppressant properties as indicated by its ability to inhibit experimental allergic encephalomyelitis, adjuvant arthritis, and the humoral (IgE) immune response [127]. Several years later, rapamycin was shown to inhibit tumor growth in xenograft models [128], an observation seemingly inconsistent with rapamycin acting as an immunosuppressant. The observation that rapamycin shares
The mTOR signaling pathway is activated in cancers
A hallmark of human cancer is deregulation of the cell cycle [146]. Consistent with the notion that the mTOR pathway is a key regulator of cell proliferation, several upstream activators and downstream effectors of mTOR are deregulated in cancers (Table 1). The two most well studied mTOR effectors are p70s6k and 4EBP1. p70s6k is overexpressed in breast cancers and is constitutively activated in several types of cancers [121], [147], [148]. Significantly, p70s6k overexpression correlates with
The mTOR pathway as a target of multiple existing anti-cancer agents
As discussed above the PI3 kinase pathway and mTOR signaling are inextricably intertwined. To complicate matters, presumed PI3K inhibitors such as wortmannin and LY294004 also inhibit mTOR [31]. Thus, the anti-proliferative, anti-cancer effects of PI3K inhibitors may be partially attributable to mTOR inactivation.
We have shown that the aspirin metabolite salicylate inhibits p70s6k activation and induces many of the same biochemical cell cycle responses as rapamycin [88]. This suggests that some
Conclusions
Rapamycin targets an evolutionarily conserved nutrient-responsive cell cycle regulatory pathway. Thus, the potent cytostatic nature of rapamycin stems from its ability to trigger a nutrient deprivation-like response. The growth inhibitory properties of rapamycin prompted researchers to explore the potential anti-cancer properties of rapamycin. It is clear from the discussion above that rapamycin is both a potent immunosuppressant and a promising anti-cancer agent. The anti-tumor efficacy of
Reviewers
Dr. Iduna Fichtner, Max-Delbrück-Centrum for Molecular Medicine, Experimental Pharmacology, Robert-Rössle-Str. 10, D-13125 Berlin-Buch, Germany.
Prof. Jaap Verweij, Department of Oncology, Erasmus University Medical Center, Postbus 5201 (Groene Hilledijk 301), NL-3008AE Rotterdam, The Netherlands.
Joon-Ho Sheen, Ph.D., Sabatini Lab, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142-1479, USA.
Robert T. Abraham, Ph.D., Professor and Director, Cancer Research
Brian Law obtained his Ph.D. in biochemistry in 1996 from Purdue University, West Lafayette, IN, USA. He is currently an assistant professor in the Department of Pharmacology and Therapeutics at the University of Florida, Gainesville, FL, USA.
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Brian Law obtained his Ph.D. in biochemistry in 1996 from Purdue University, West Lafayette, IN, USA. He is currently an assistant professor in the Department of Pharmacology and Therapeutics at the University of Florida, Gainesville, FL, USA.