IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms

• Published in: Cancer biology & therapy Vol. 6; no. 4; pp. 534 - 540
• Main Authors: Takaoka, Munenori, Kim, Seok-Hyun, Okawa, Takaomi, Michaylira, Carmen Z., Stairs, Doug, Johnston, Cameron, Andl, Claudia D., Rhoades, Ben, Lee, James, Klein-Szanto, Andres, El-Deiry, Wafik S., Nakagawa, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.04.2007
• Subjects: Animals; Apoptosis; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Line, Tumor; Cycle; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Humans; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-Like Growth Factor Binding Protein 3 - physiology; Insulin-Like Growth Factor I - metabolism; Landes; Mice; Mice, Nude; Mutation; Neoplasm Transplantation; Organogenesis; Proteins; Receptor, IGF Type 1 - agonists; Receptor, IGF Type 1 - metabolism
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.6.4.3832

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-RasV12-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-I 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.