Abstract
Transforming growth factor-beta (TGF-beta) signaling facilitates tumor growth and metastasis in advanced cancer. In the present study, we identified differentially expressed in chondrocytes 1 (DEC1, also known as SHARP2 and Stra13) as a downstream target of TGF-beta signaling, which promotes the survival of breast cancer cells. In the mouse mammary carcinoma cell lines JygMC(A) and 4T1, the TGF-beta type I receptor kinase inhibitors A-44-03 and SB431542 induced apoptosis of cells under serum-free conditions. Oligonucleotide microarray and real-time reverse transcription-PCR analyses revealed that TGF-beta induced DEC1 in these cells, and the increase of DEC1 was suppressed by the TGF-beta type I receptor kinase inhibitors as well as by expression of dominant-negative TGF-beta type II receptor. Overexpression of DEC1 prevented the apoptosis of JygMC(A) cells induced by A-44-03, and knockdown of endogenous DEC1 abrogated TGF-beta-promoted cell survival. Moreover, a dominant-negative mutant of DEC1 prevented lung and liver metastasis of JygMC(A) cells in vivo. Our observations thus provide new insights into the molecular mechanisms governing TGF-beta-mediated cell survival and metastasis of cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology
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Basic Helix-Loop-Helix Transcription Factors / biosynthesis
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Cell Survival / physiology
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / genetics
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Humans
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Liver Neoplasms / secondary
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Lung Neoplasms / secondary
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology*
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Mice
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Platelet-Derived Growth Factor / metabolism
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Signal Transduction
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Smad Proteins / metabolism
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta / pharmacology
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Tumor Suppressor Proteins / biosynthesis*
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Tumor Suppressor Proteins / genetics
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Bhlhe40 protein, mouse
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DELEC1 protein, human
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Homeodomain Proteins
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Protein Kinase Inhibitors
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RNA, Messenger
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Transforming Growth Factor beta
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Tumor Suppressor Proteins
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Receptors, Platelet-Derived Growth Factor
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Receptor, Transforming Growth Factor-beta Type I