mTOR and cancer: many loops in one pathway
Introduction
Adequate cellular levels of energy and nutrients are a prerequisite for successful cell growth and division. Therefore, cells have acquired mechanisms to sense energy and nutrients before committing to grow and divide. In all eukaryotes, the target of rapamycin (TOR) protein is a master regulator that integrates the signals from nutrient and energy sensors with cell growth and proliferation, so as to ensure that they are triggered only during favorable conditions. The mammalian TOR (mTOR) also integrates growth factor signaling together with nutrients and energy as a mechanism to coordinate cell growth and proliferation in large number of cells within different organs. In addition to this, a network of regulatory loops affects the function of mTOR and impact on therapeutic approaches aimed at targeting mTOR, which will be discussed here.
Section snippets
The mTOR signaling pathway
mTOR forms two different protein complexes defined by the proteins to which it is bound, exerting different but related functions. The mTOR complex 1 (mTORC1) is defined by the presence of Raptor, mLST8/GβL, Deptor, and PRAS40 [1, 2, 3, 4, 5•, 6, 7], whereas Rictor, GβL, Protor, Deptor, and mSin form mTORC2 [8, 9, 10, 11, 12] (see Figure 1). In addition to their differential sensitivity to rapamycin, mTORC1 and 2 are activated in different ways and have distinct substrate specificity. mTORC1,
Complex loops of regulation — all roads lead to mTOR
mTOR, as a master regulator of a variety of inputs, is subjected to different mechanisms that tightly and coordinately regulate its activation. Many positive and feedback loops have been described lately and most likely other regulatory loops will be deciphered in the near future.
Rapamycin-based therapy
Extensive basic research with rapamycin showed high specificity toward mTORC1 inhibition. This has encouraged a number of clinical trials using this compound as an anticancer drug, but in fact, rapamycin and its first generation analogs temsirolimus and everolimus have proven modest success in clinical trials, reflecting an incomplete understanding of mTOR functions. These small molecules are allosteric inhibitors of mTOR that block S6K1 phosphorylation, but it has become evident that not all
Conclusions
In the last years, substantial progression in the understanding of how mTOR signaling pathway occurs has taught us that there are still significant aspects of mTOR regulation that need further clarification. The mechanism underlying the induction of cell death versus cell-cycle arrest in different cell lines treated with mTOR inhibitors, the existence of additional feedback loops triggered by S6K1 and how these loops affect therapeutic responses should be addressed in the future. Moreover, a
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank NIH and HHMI for funding our work on mTOR. A.E. is supported by the Human Frontiers Science Program.
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