Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors.
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.
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA and.
Theresa D
TD
Carr
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA and.
Robert P
RP
Feehan
Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Michael N
MN
Hall
Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Markus A
MA
Rüegg
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA and lms17@psu.edu.
Lisa M
LM
Shantz
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002273:Carcinogens / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D018890:Chemoprevention; D015603:Keratinocytes / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects
D002273:Carcinogens; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D013755:Tetradecanoylphorbol Acetate