In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. LB-5-LB-5
Abstract:
Insulin-like growth factor-1 (IGF1) is a major therapeutic target for cancer. Integrin αvβ3 plays a critical role in regulating IGF1 signaling, while the specifics are unclear. We recently reported that IGF1 directly binds to αvβ3. The integrin-binding defective IGF1 mutant (R36E/R37E) is defective in inducing IGF signaling and a ternary complex (αvβ3, IGF1R, and IGF1) formation, although the mutant still binds to the type 1 IGF receptor (IGF1R). These findings suggest that direct binding of IGF1 to αvβ3 is required for intracellular signaling (J. Saegusa, S. Yamaji, K. Ieguchi, C.Y. Wu, K.S. Lam, F.T. Liu, Y.K. Takada, and Y. Takada, The direct binding of insulin-like growth factor-1 (IGF-1) to integrin αvβ3 is involved in IGF-1 signaling. J Biol Chem, 2009. 284: 24106–14). Here we describe that R36E/R37E suppressed proliferation and intracellular signaling induced by WT IGF1 in NIH3T3 fibroblasts, C2C12 myoblasts, and MCF-7 breast cancer cells (a dominant negative effect). R36E/R37E suppressed anchorage-independent growth of MCF-7 cells, while WT IGF1 enhanced it. Also, R36E/R37E suppressed the tumorigenesis of MCF-7 cells in SCID mice, while wt IGF-1 markedly enhanced it. Since MCF-7 cells express little or no αvβ3, we studied which integrins are involved in IGF signaling. We discovered that α6β4, which is over-expressed in cancer and implicated in tumor progression, directly binds to WT IGF1 (but not to R36E/R37E) in MCF-7. Interestingly, WT IGF1 induced a ternary complex formation (α6β4, IGF1, and IGF1R) but R36E/R37E did not. These results suggest that α6β4 in addition to αvβ3 plays a role in IGF signaling through direct binding to IGF1, and that R36E/R37E acts as an inhibitor of IGF signaling. We propose that R36E/R37E has potential as a therapeutic agent in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-5. doi:10.1158/1538-7445.AM2011-LB-5
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-LB-5
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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