IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms. Cancer Biol Ther 2007 Apr;6(4):534-40
Date
04/26/2007Pubmed ID
17457048Pubmed Central ID
PMC2993006DOI
10.4161/cbt.6.4.3832Scopus ID
2-s2.0-34548218999 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
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.
Author List
Takaoka M, Kim SH, Okawa T, Michaylira CZ, Stairs DB, Johnstone CN, Andl CD, Rhoades B, Lee JJ, Klein-Szanto AJ, El-Deiry WS, Nakagawa HMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cell Line, Tumor
Esophageal Neoplasms
Humans
Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I
Mice
Mice, Nude
Mutation
Neoplasm Transplantation
Receptor, IGF Type 1
