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PMID: 12417722 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells.

Molecular and cellular biology ·Vol. 22 ·No. 23 ·2002-12-00 ·Pages 8184-98

Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, Covington C, Moses HL

Abstract

Transforming growth factor beta (TGF-beta) induces cell cycle arrest of most nontransformed epithelial cell lines. In contrast, many human carcinomas are refractory to the growth-inhibitory effect of TGF-beta. TGF-beta overexpression inhibits tumorigenesis, and abolition of TGF-beta signaling accelerates tumorigenesis, suggesting that TGF-beta acts as a tumor suppressor in mouse models of cancer. A screen to identify agents that potentiate TGF-beta-induced growth arrest demonstrated that the potential anticancer agent rapamycin cooperated with TGF-beta to induce growth arrest in multiple cell lines. Rapamycin also augmented the ability of TGF-beta to inhibit the proliferation of E2F1-, c-Myc-, and (V12)H-Ras-transformed cells, even though these cells were insensitive to TGF-beta-mediated growth arrest in the absence of rapamycin. Rapamycin potentiation of TGF-beta-induced growth arrest could not be explained by increases in TGF-beta receptor levels or rapamycin-induced dissociation of FKBP12 from the TGF-beta type I receptor. Significantly, TGF-beta and rapamycin cooperated to induce growth inhibition of human carcinoma cells that are resistant to TGF-beta-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 Thr(160). 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-beta cooperate to inhibit the proliferation of nontransformed cells and cancer cells by acting in concert to inhibit Cdk2 activity.

MeSH Terms
Animals Antibiotics, Antineoplastic/metabolism CDC2-CDC28 Kinases Carcinoma/metabolism Cell Cycle Proteins/metabolism Cell Division/physiology Cell Line Cell Transformation, Neoplastic Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases/metabolism Cyclins/metabolism DNA-Binding Proteins/metabolism E2F4 Transcription Factor Enzyme Inhibitors/metabolism Epithelial Cells/physiology Genes, Reporter Growth Inhibitors/metabolism Humans Nuclear Proteins/metabolism Phosphoproteins/metabolism Protein Binding Protein Serine-Threonine Kinases/metabolism Proteins Retinoblastoma Protein/metabolism Retinoblastoma-Like Protein p107 Retinoblastoma-Like Protein p130 Signal Transduction/physiology Sirolimus/metabolism Tacrolimus Binding Proteins/metabolism Transcription Factors/metabolism Transforming Growth Factor beta/metabolism Tumor Suppressor Proteins/metabolism
Chemicals
Antibiotics, Antineoplastic CDKN1A protein, human Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p21 Cyclins DNA-Binding Proteins E2F4 Transcription Factor Enzyme Inhibitors Growth Inhibitors Nuclear Proteins Phosphoproteins Proteins RBL1 protein, human Rbl1 protein, mouse Retinoblastoma Protein Retinoblastoma-Like Protein p107 Retinoblastoma-Like Protein p130 Transcription Factors Transforming Growth Factor beta Tumor Suppressor Proteins Cyclin-Dependent Kinase Inhibitor p27 Protein Serine-Threonine Kinases CDC2-CDC28 Kinases CDK2 protein, human Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases Tacrolimus Binding Proteins Sirolimus
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Law Brian K
Department of Cancer Biology. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. brian.k.law@vanderbilt.edu
Chytil Anna
Dumont Nancy
Hamilton Elizabeth G
Waltner-Law Mary E
Aakre Mary E
Covington Cassondra
Moses Harold L
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.23.8184-8198.2002
Email
brian.k.law@vanderbilt.edu
Published
2002-12-00
Pages
8184-98
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC134072
Subset
IM
Grants
NCI NIH HHS · P30 CA068485 · United States
NCI NIH HHS · CA85492 · United States
NCI NIH HHS · CA68485 · United States
NCI NIH HHS · R01 CA085492 · United States
NCI NIH HHS · CA42572 · United States
External Links
PubMed source DOI: 10.1128/MCB.22.23.8184-8198.2002 PMC Full Text View journal details
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