Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors

Theresa D. Carr, Robert P. Feehan, Michael N. Hall, Markus A. Rüegg, Lisa M. Shantz

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Activation of signaling dependent on the mammalian target of rapamycin (mTOR) has been demonstrated in a variety of human malignancies, and our previous work suggests that mTOR complex (mTORC) 1 and mTORC2 may play unique roles in skin tumorigenesis. The purpose of these studies was to investigate the function of mTORC2-dependent pathways in skin tumor development and the maintenance of established tumors. Using mice that allow spatial and temporal control of mTORC2 in epidermis by conditional knockout of its essential component Rictor, we studied the effect of mTORC2 loss on both epidermal proliferation and chemical carcinogenesis. The results demonstrate that mTORC2 is dispensable for both normal epidermal proliferation and the hyperproliferative response to treatment with tetradecanoyl phorbol acetate (TPA). In contrast, deletion of epidermal Rictor prior to initiation in DMBA/TPA chemical carcinogenesis was sufficient to dramatically delay tumor development and resulted in reduced tumor number and size compared with control groups. Silencing of Rictor expression in tumor-bearing animals triggered regression of established tumors and increased caspase-3 cleavage without changes in proliferation. In vitro experiments demonstrate an increased sensitivity to caspase-dependent apoptosis in the absence of rictor, which is dependent on mTORC2 signaling. These studies demonstrate that mTORC2 activation is essential for keratinocyte survival, and suggest that inhibition of mTORC2 has value in chemoprevention by eliminating carcinogen-damaged cells during the early stages of tumorigenesis, and in therapy of existing tumors by restricting critical pro-survival pathways.

Original languageEnglish (US)
Pages (from-to)487-497
Number of pages11
JournalCarcinogenesis
Volume36
Issue number4
DOIs
StatePublished - Jul 10 2014

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Growth and Development
Skin
Neoplasms
Carcinogenesis
Acetates
9,10-Dimethyl-1,2-benzanthracene
TOR complex 2
Chemoprevention
Sirolimus
Caspases
Keratinocytes
Epidermis
Caspase 3
Carcinogens
Maintenance
Apoptosis
Control Groups
Survival
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Carr, Theresa D. ; Feehan, Robert P. ; Hall, Michael N. ; Rüegg, Markus A. ; Shantz, Lisa M. / Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors. In: Carcinogenesis. 2014 ; Vol. 36, No. 4. pp. 487-497.
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Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors. / Carr, Theresa D.; Feehan, Robert P.; Hall, Michael N.; Rüegg, Markus A.; Shantz, Lisa M.

In: Carcinogenesis, Vol. 36, No. 4, 10.07.2014, p. 487-497.

Research output: Contribution to journalArticle

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