Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis

B Tassone, S Saoncella, Francesco Neri, U Ala, Davide Brusa, MA Magnuson, P Provero, Salvatore Oliviero, Chiara Riganti, E Calautti

Research output: Contribution to journalArticle

Abstract

How metabolic pathways required for epidermal tissue growth and remodeling influence the ability of keratinocytes to survive stressful conditions is still largely unknown. The mechanistic target of rapamycin complex 2 (mTORC2) regulates growth and metabolism of several tissues, but its functions in epidermal cells are poorly defined. Rictor is an adaptor protein essential for mTORC2 activity. To explore the roles of mTORC2 in the epidermis, we have conditionally deleted rictor in mice via K14-Cre-mediated homologous recombination and found that its deficiency causes moderate tissue hypoplasia, reduced keratinocyte proliferation and attenuated hyperplastic response to TPA. Noteworthy, rictor-deficient keratinocytes displayed increased lifespan, protection from senescence, and enhanced tolerance to cellular stressors such as growth factors deprivation, epirubicin and X-ray in vitro and radioresistance in vivo. Rictor-deficient keratinocytes exhibited changes in global gene expression profiles consistent with metabolic alterations and enhanced stress tolerance, a shift in cell catabolic processes from glycids and lipids to glutamine consumption and increased production of mitochondrial reactive oxygen species (ROS). Mechanistically, the resiliency of rictor-deficient epidermal cells relies on these ROS increases, indicating stress resistance via mitohormesis. Thus, our findings reveal a new link between metabolic changes and stress adaptation of keratinocytes centered on mTORC2 activity, with potential implications in skin aging and therapeutic resistance of epithelial tumors. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Original languageEnglish
Pages (from-to)731-746
Number of pages16
JournalCell Death and Differentiation
Volume24
Issue number4
DOIs
Publication statusPublished - 2017

Fingerprint

Keratinocytes
Reactive Oxygen Species
Skin Aging
Epirubicin
Homologous Recombination
Growth
Metabolic Networks and Pathways
Glutamine
Transcriptome
Epidermis
Intercellular Signaling Peptides and Proteins
X-Rays
TOR complex 2
Lipids
Neoplasms
Proteins
Therapeutics

Cite this

Tassone, B., Saoncella, S., Neri, F., Ala, U., Brusa, D., Magnuson, MA., ... Calautti, E. (2017). Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis. Cell Death and Differentiation, 24(4), 731-746. https://doi.org/10.1038/cdd.2017.8

Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis. / Tassone, B; Saoncella, S; Neri, Francesco; Ala, U; Brusa, Davide; Magnuson, MA; Provero, P; Oliviero, Salvatore; Riganti, Chiara; Calautti, E.

In: Cell Death and Differentiation, Vol. 24, No. 4, 2017, p. 731-746.

Research output: Contribution to journalArticle

Tassone, B, Saoncella, S, Neri, F, Ala, U, Brusa, D, Magnuson, MA, Provero, P, Oliviero, S, Riganti, C & Calautti, E 2017, 'Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis', Cell Death and Differentiation, vol. 24, no. 4, pp. 731-746. https://doi.org/10.1038/cdd.2017.8
Tassone, B ; Saoncella, S ; Neri, Francesco ; Ala, U ; Brusa, Davide ; Magnuson, MA ; Provero, P ; Oliviero, Salvatore ; Riganti, Chiara ; Calautti, E. / Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis. In: Cell Death and Differentiation. 2017 ; Vol. 24, No. 4. pp. 731-746.
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AB - How metabolic pathways required for epidermal tissue growth and remodeling influence the ability of keratinocytes to survive stressful conditions is still largely unknown. The mechanistic target of rapamycin complex 2 (mTORC2) regulates growth and metabolism of several tissues, but its functions in epidermal cells are poorly defined. Rictor is an adaptor protein essential for mTORC2 activity. To explore the roles of mTORC2 in the epidermis, we have conditionally deleted rictor in mice via K14-Cre-mediated homologous recombination and found that its deficiency causes moderate tissue hypoplasia, reduced keratinocyte proliferation and attenuated hyperplastic response to TPA. Noteworthy, rictor-deficient keratinocytes displayed increased lifespan, protection from senescence, and enhanced tolerance to cellular stressors such as growth factors deprivation, epirubicin and X-ray in vitro and radioresistance in vivo. Rictor-deficient keratinocytes exhibited changes in global gene expression profiles consistent with metabolic alterations and enhanced stress tolerance, a shift in cell catabolic processes from glycids and lipids to glutamine consumption and increased production of mitochondrial reactive oxygen species (ROS). Mechanistically, the resiliency of rictor-deficient epidermal cells relies on these ROS increases, indicating stress resistance via mitohormesis. Thus, our findings reveal a new link between metabolic changes and stress adaptation of keratinocytes centered on mTORC2 activity, with potential implications in skin aging and therapeutic resistance of epithelial tumors. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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