期刊
CANCER BIOLOGY & THERAPY
卷 6, 期 4, 页码 534-540出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.6.4.3832
关键词
IGFBP-3; IGF; Ras; esophageal cancer; in vivo bioluminescence
类别
资金
- NCI NIH HHS [P01-CA-098101, P01 CA098101] Funding Source: Medline
- NIDDK NIH HHS [K01-DK-066205, K01 DK075379-01A1, K01 DK075379, K01 DK066205] Funding Source: Medline
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 Ile(56), Leu(80), and Leu(81) 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.
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