Smad6 suppresses TGF-beta-induced growth inhibition in COLO-357 pancreatic cancer cells and is overexpressed in pancreatic cancer.
Transforming growth factor (TGF)-beta signaling is initiated by heterodimerization of TGF-beta receptor type I (TbetaRI) and type II (TbetaRII). Subsequently, the signal is transduced via Smad proteins, which upon phosphorylation and heterodimerization translocate to the nucleus and regulate gene transcription. Smad6 functions as an intracellular antagonist of TGF-beta signaling. In the present study we demonstrate that Smad6 is overexpressed in vivo in human pancreatic cancer cells. We also show that stable transfection of a full-length Smad6 construct into COLO-357 pancreatic cancer cells abrogates TGF-beta1 induced growth inhibition, and leads to enhanced anchorage-independent growth. Thus, enhanced expression of the TGF-beta signaling inhibitor Smad6 in pancreatic cancer may present a novel mechanism of TGF-beta resistance, which might have the potential to enhance the transformed phenotype of human cancer cells.
Department of Medicine, University of California, Irvine 92697, USA.
J
J
Kleeff
H
H
Maruyama
H
H
Friess
M W
MW
Büchler
D
D
Falb
M
M
Korc
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D005260:Female; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051905:Smad6 Protein; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C497802:SMAD6 protein, human; D051905:Smad6 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta