Transforming growth factor-beta promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1.
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.
Ehata
Shogo
S
Department of Biochemistry, Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, Japan.
Hanyu
Aki
A
Hayashi
Makoto
M
Aburatani
Hiroyuki
H
Kato
Yukio
Y
Fujime
Makoto
M
Saitoh
Masao
M
Miyazawa
Keiji
K
Imamura
Takeshi
T
Miyazono
Kohei
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000077293:Receptor, Transforming Growth Factor-beta Type I; D017479:Receptors, Platelet-Derived Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C491539:Bhlhe40 protein, mouse; C403671:DELEC1 protein, human