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

Munenori Takaoka, Seok Hyun Kim, Takaomi Okawa, Carmen Z. Michaylira, Douglas B. Stairs, Cameron N. Johnstone, Claudia D. Andl, Ben Rhoades, James J. Lee, Andres J.P. Klein-Szanto, Wafik S. El-Deiry, Hiroshi Nakagawa

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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, Leu 80, 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.

Original languageEnglish (US)
Pages (from-to)534-540
Number of pages7
JournalCancer Biology and Therapy
Volume6
Issue number4
DOIs
StatePublished - Apr 2007

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Fingerprint Dive into the research topics of 'IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms'. Together they form a unique fingerprint.

  • Cite this

    Takaoka, M., Kim, S. H., Okawa, T., Michaylira, C. Z., Stairs, D. B., Johnstone, C. N., Andl, C. D., Rhoades, B., Lee, J. J., Klein-Szanto, A. J. P., El-Deiry, W. S., & Nakagawa, H. (2007). IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms. Cancer Biology and Therapy, 6(4), 534-540. https://doi.org/10.4161/cbt.6.4.3832