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Molecular and Cellular Biology, December 2002, p. 8184-8198, Vol. 22, No. 23
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.23.8184-8198.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Rapamycin Potentiates Transforming Growth Factor ß-Induced Growth Arrest in Nontransformed, Oncogene-Transformed, and Human Cancer Cells

Brian K. Law,1* Anna Chytil,1 Nancy Dumont,1 Elizabeth G. Hamilton,1 Mary E. Waltner-Law,2 Mary E. Aakre,1 Cassondra Covington,1 and Harold L. Moses1

Department of Cancer Biology,1 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 372322

Received 16 July 2002/ Accepted 5 September 2002

Transforming growth factor ß (TGF-ß) induces cell cycle arrest of most nontransformed epithelial cell lines. In contrast, many human carcinomas are refractory to the growth-inhibitory effect of TGF-ß. TGF-ß overexpression inhibits tumorigenesis, and abolition of TGF-ß signaling accelerates tumorigenesis, suggesting that TGF-ß acts as a tumor suppressor in mouse models of cancer. A screen to identify agents that potentiate TGF-ß-induced growth arrest demonstrated that the potential anticancer agent rapamycin cooperated with TGF-ß to induce growth arrest in multiple cell lines. Rapamycin also augmented the ability of TGF-ß to inhibit the proliferation of E2F1-, c-Myc-, and V12H-Ras-transformed cells, even though these cells were insensitive to TGF-ß-mediated growth arrest in the absence of rapamycin. Rapamycin potentiation of TGF-ß-induced growth arrest could not be explained by increases in TGF-ß receptor levels or rapamycin-induced dissociation of FKBP12 from the TGF-ß type I receptor. Significantly, TGF-ß and rapamycin cooperated to induce growth inhibition of human carcinoma cells that are resistant to TGF-ß-induced growth arrest, and arrest correlated with a suppression of Cdk2 kinase activity. Inhibition of Cdk2 activity was associated with increased binding of p21 and p27 to Cdk2 and decreased phosphorylation of Cdk2 on Thr160. Increased p21 and p27 binding to Cdk2 was accompanied by decreased p130, p107, and E2F4 binding to Cdk2. Together, these results indicate that rapamycin and TGF-ß cooperate to inhibit the proliferation of nontransformed cells and cancer cells by acting in concert to inhibit Cdk2 activity.

* Corresponding author. Mailing address: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 612 Preston Research Building, Nashville, TN 37232. Phone: (615) 936-1507. Fax: (615) 936-1790. E-mail: brian.k.law{at}vanderbilt.edu.

Molecular and Cellular Biology, December 2002, p. 8184-8198, Vol. 22, No. 23
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.23.8184-8198.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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