Tuberous Sclerosis-associated Neoplasms Express Activated p42/44 Mitogen-activated Protein (MAP) Kinase, and Inhibition of MAP Kinase Signaling Results in Decreased in Vivo Tumor Growth

Tuberous Sclerosis-associated Neoplasms Express Activated p42/44 Mitogen-activated Protein (MAP) Kinase, and Inhibition of MAP Kinase Signaling Results in Decreased in Vivo Tumor Growth1

Departments of Dermatology [B. G., M. N., K. C., J. L. A.], Pathology [D. B., C. C.], and Emory Skin Disease Research Center, Emory University School of Medicine, Atlanta, Georgia 30322; Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina [M. C. M., M. S. M.]; and Division of Hematology/Oncology, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115 [H. O.]

Abstract

Purpose: Tuberous sclerosis (TS) is a common autosomal disorder attributable to inactivation of the tumor suppressor genes tuberin and hamartin. To determine whether mitogen-activated protein (MAP) kinase signaling plays a role in the pathogenesis of TS, we stained human TS-associated neoplasms with antibodies directed against activated MAP kinase, and observed high-level expression.

Experimental Design: To determine whether MAP kinase is functionally important for the development of neoplasia in TS, we established a murine model of TS-associated neoplasia (Tsc2Ang1 cells) from a tumor arising in a mouse heterozygous for tuberin. Tsc2Ang1 cells demonstrate tumorigenesis in vivo and high-level expression of activated MAP kinase in vitro. The functionality of MAP kinase signaling was assessed by inactivating MAP kinase using a dominant-negative MAP kinase kinase in tsc2ang1 cells and assessing the effect of this intervention on in vivo tumorigenicity and production of the potent angiogenic factor vascular endothelial growth factor (VEGF).

Results: Human TS-related neoplasms demonstrate high-level expression of activated MAP kinase, as does a tumor arising in a mouse heterozygous for tuberin. The inhibition of MAP kinase signaling by the introduction of a dominant-negative MAP kinase kinase leads to the inhibition of tumor growth in vivo and decreased production of VEGF.

Conclusions: MAP kinase is activated in TS-related neoplasia in mice and humans. Inhibition of MAP kinase leads to decreased tumor growth in vivo. Pharmacological inhibition of MAP kinase may be a therapeutic target in the prevention and treatment of TS-related tumors.

Footnotes

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↵1 Supported by the Tuberous Sclerosis Alliance and NIH Grants AR02030, RO1 AR47901, and National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIAMS) Emory Skin Disease Research Core Center P30 AR42687 (to J. L. A.), and Grants RO1 ES06501 and ES08252 (to M. S. M.) from the National Institute of Environmental Health Sciences and Cancer Center Support Grant P30 CA12197 from the National Cancer Institute, which provided support for the Wake Forest University Analytical Imaging Core Facility, the DNA Synthesis Core Laboratory, and the DNA Sequencing and Gene Analysis Facility.
↵2 To whom requests for reprints should be addressed, at Department of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Drive, Atlanta, GA 30322. Phone: (404) 727-5063; Fax: (404) 727-0923; E-mail: jarbise{at}emory.edu
↵3 The abbreviations used are: TS, tuberous sclerosis; LOH, loss of heterozygosity; NF1, neurofibromatosis type 1; MPNST, malignant peripheral nerve sheath tumor; EGF, epidermal growth factor; EGFR, EGF receptor; GFP, green fluorescent protein; MAP, mitogen-activated protein; MAPK, MAP kinase; MAPKK, MAPK kinase; VEGF, vascular endothelial growth factor; PI3 kinase, phosphatidylinositol 3′-kinase; PDGFR2χ platelet-derived growth factor receptor β.
↵4 Peter Crino, University of Pennsylvania, personal communication.
- Accepted April 14, 1903.
- Received October 21, 1902.
- Revision received March 24, 1903.