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Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer

Mohammadreza Dorvash, Mohammad Farahmandnia, Pouria Mosaddeghi, Mitra Farahmandnejad, Hosein Saber, Mohammadhossein Khorraminejad-Shirazi, Amir Azadi, View ORCID ProfileIman Tavassoly
doi: https://doi.org/10.1101/633891
Mohammadreza Dorvash
1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2Cell and Molecular Medicine Student Research Group, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Mohammad Farahmandnia
2Cell and Molecular Medicine Student Research Group, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
3Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
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Pouria Mosaddeghi
1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2Cell and Molecular Medicine Student Research Group, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
3Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
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Mitra Farahmandnejad
1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2Cell and Molecular Medicine Student Research Group, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
3Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
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Hosein Saber
1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
3Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
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Mohammadhossein Khorraminejad-Shirazi
2Cell and Molecular Medicine Student Research Group, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
3Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
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Amir Azadi
1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
4Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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Iman Tavassoly
5Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
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  • ORCID record for Iman Tavassoly
  • For correspondence: iman.tavassoly@mssm.edu
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Abstract

Signal integration in the mTOR pathway plays a vital role in cell fate decision making in cancer cells. As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein. 2-Components like Phosphatidic Acid further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier’s principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. The model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin.

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Posted May 10, 2019.
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Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer
Mohammadreza Dorvash, Mohammad Farahmandnia, Pouria Mosaddeghi, Mitra Farahmandnejad, Hosein Saber, Mohammadhossein Khorraminejad-Shirazi, Amir Azadi, Iman Tavassoly
bioRxiv 633891; doi: https://doi.org/10.1101/633891
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Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer
Mohammadreza Dorvash, Mohammad Farahmandnia, Pouria Mosaddeghi, Mitra Farahmandnejad, Hosein Saber, Mohammadhossein Khorraminejad-Shirazi, Amir Azadi, Iman Tavassoly
bioRxiv 633891; doi: https://doi.org/10.1101/633891

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