IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms.
Insulin-like growth factor binding protein (IGFBP)-3 exerts either proapoptotic or growth stimulatory effects depending upon the cellular context. IGFBP-3 is overexpressed frequently in esophageal cancer. Yet, the role of IGFBP-3 in esophageal tumor biology remains elusive. To delineate the functional consequences of IGFBP-3 overexpression, we stably transduced Ha-Ras(V12)-transformed human esophageal cells with either wild-type or mutant IGFBP-3, the latter incapable of binding Insulin-like growth factor (IGFs) as a result of substitution of amino-terminal Ile56, Leu80, and Leu81 residues with Glycine residues. Wild-type, but not mutant, IGFBP-3 prevented IGF-1 from activating the IGF-1 receptor and AKT, and suppressed anchorage-independent cell growth. When xenografted in nude mice, in vivo bioluminescence imaging demonstrated that wild-type, but not mutant IGFBP-3, abrogated tumor formation by the Ras-transformed cells with concurrent induction of apoptosis, implying a prosurvival effect of IGF in cancer cell adaptation to the microenvironment. Moreover, there was more aggressive tumor growth by mutant IGFBP-3 overexpressing cells than control cell tumors, without detectable caspase-3 cleavage in tumor tissues, indicating an IGF-independent growth stimulatory effect of mutant IGFBP-3. In aggregate, these data suggest that IGFBP-3 contributes to esophageal tumor development and progression through IGF-dependent and independent mechanisms.
Takaoka
Munenori
M
Gastroengerology Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Kim
Seok-Hyun
SH
Okawa
Takaomi
T
Michaylira
Carmen Z
CZ
Stairs
Douglas B
DB
Johnstone
Cameron N
CN
Andl
Claudia D
CD
Rhoades
Ben
B
Lee
James J
JJ
Klein-Szanto
Andres J P
AJ
El-Deiry
Wafik S
WS
Nakagawa
Hiroshi
H
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D017526:Receptor, IGF Type 1 / Q000819:agonists / Q000378:metabolism
D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1