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

Munenori Takaoka, Seok Hyun Kim, Takaomi Okawa, Carmen Z. Michaylira, Douglas 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 Citations (Scopus)

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 - Jan 1 2007

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Insulin-Like Growth Factor Binding Protein 3
Somatomedins
Growth
Neoplasms
Somatomedin Receptors
Esophageal Neoplasms
Insulin-Like Growth Factor I
Nude Mice
Caspase 3
Glycine
Apoptosis

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Takaoka, M., Kim, S. H., Okawa, T., Michaylira, C. Z., Stairs, D., Johnstone, C. N., ... 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
Takaoka, Munenori ; Kim, Seok Hyun ; Okawa, Takaomi ; Michaylira, Carmen Z. ; Stairs, Douglas ; Johnstone, Cameron N. ; Andl, Claudia D. ; Rhoades, Ben ; Lee, James J. ; Klein-Szanto, Andres J.P. ; El-Deiry, Wafik S. ; Nakagawa, Hiroshi. / IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms. In: Cancer Biology and Therapy. 2007 ; Vol. 6, No. 4. pp. 534-540.
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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.",
author = "Munenori Takaoka and Kim, {Seok Hyun} and Takaomi Okawa and Michaylira, {Carmen Z.} and Douglas Stairs and Johnstone, {Cameron N.} and Andl, {Claudia D.} and Ben Rhoades and Lee, {James J.} and Klein-Szanto, {Andres J.P.} and El-Deiry, {Wafik S.} and Hiroshi Nakagawa",
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Takaoka, M, Kim, SH, Okawa, T, Michaylira, CZ, Stairs, D, Johnstone, CN, Andl, CD, Rhoades, B, Lee, JJ, Klein-Szanto, AJP, El-Deiry, WS & Nakagawa, H 2007, 'IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms', Cancer Biology and Therapy, vol. 6, no. 4, pp. 534-540. https://doi.org/10.4161/cbt.6.4.3832

IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms. / Takaoka, Munenori; Kim, Seok Hyun; Okawa, Takaomi; Michaylira, Carmen Z.; Stairs, Douglas; Johnstone, Cameron N.; Andl, Claudia D.; Rhoades, Ben; Lee, James J.; Klein-Szanto, Andres J.P.; El-Deiry, Wafik S.; Nakagawa, Hiroshi.

In: Cancer Biology and Therapy, Vol. 6, No. 4, 01.01.2007, p. 534-540.

Research output: Contribution to journalArticle

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T1 - IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms

AU - Takaoka, Munenori

AU - Kim, Seok Hyun

AU - Okawa, Takaomi

AU - Michaylira, Carmen Z.

AU - Stairs, Douglas

AU - Johnstone, Cameron N.

AU - Andl, Claudia D.

AU - Rhoades, Ben

AU - Lee, James J.

AU - Klein-Szanto, Andres J.P.

AU - El-Deiry, Wafik S.

AU - Nakagawa, Hiroshi

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Y1 - 2007/1/1

N2 - 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.

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