Type III transforming growth factor-beta (TGF-beta) receptor mediates apoptosis in renal cell carcinoma independent of the canonical TGF-beta signaling pathway.
OBJECTIVE
Alterations in transforming growth factor-beta (TGF-beta) signaling occur early during malignant transformation of renal epithelial cells and are associated with loss of type III TGF-beta receptor (TbetaRIII) expression. We evaluated the role of TbetaRIII in mediation of apoptosis using in vitro cell culture and in vivo animal models of clear cell renal cell carcinoma.


METHODS
TbetaR3 expression was manipulated with adenoviral gene vector delivery system in vitro and in vivo. Induction of apoptosis and signaling through the Smad and mitogen-activated protein kinase (MAPK) pathways were examined at various time points after infection. To study viral oncolysis in vivo, human renal cell carcinoma cells were implanted s.c. in the flanks of nude mice and treated with intratumoral injections of adenovirus.


RESULTS
Restoring TbetaRIII expression in clear cell renal cell carcinoma resulted in a marked induction of apoptosis using in vitro cell culture and in vivo animal models. The expression of the cytoplasmic domain, but not the extracellular domain, of TbetaRIII mimicked the induction of apoptosis by full-length TbetaRIII in cell culture and the growth inhibition of tumors in athymic nude mice. TbetaRIII-associated apoptosis was not dependent on signaling through the canonical TGF-beta/Smad pathway but was mediated through p38 MAPK.


CONCLUSIONS
These findings indicate a novel mechanistic antitumor function for TbetaRIII and further support its role as an important tumor suppressor in clear cell renal cell carcinoma.
Margulis
Vitaly
V
Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Maity
Tapati
T
Zhang
Xiu-Ying
XY
Cooper
Simon J
SJ
Copland
John A
JA
Wood
Christopher G
CG
D000818:Animals; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases
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