Journal
CANCER LETTERS
Volume 325, Issue 2, Pages 200-206Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2012.07.004
Keywords
GRP78; IGFBP-3; Caspase-7; Apoptosis; Breast cancer; Drug-resistance
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Funding
- Department of Defense Grant [W81XWH-09-1-0061]
- NIH-NCI Cancer Center Support Grant [P30 CA016059]
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IGFBP-3 is known to possess intrinsic biological activities such as anti-tumor property in addition to its IGF/IGF-R axis-dependent actions in a variety of human cancers including breast cancer. To investigate the molecular mechanisms underlying the intrinsic biological actions of IGFBP-3 on breast cancer cells, we performed yeast two-hybrid screening and found GRP78, known to cause drug-resistance, as a binding partner of IGFBP-3. Overexpression of IGFBP-3 in antiestrogen-resistant LCC9 cells showed that IGFBP-3 interacted with GRP78, resulting in disruption of the GRP78-caspase-7 complex, thereby activating caspase-7, and further inducing apoptosis. Combination of overexpression of IGFBP-3 and application of siRNAs against GRP78 led to decrease in cell viability upon ICI 182,780 treatment. These data suggest that IGFBP-3 could sensitize antiestrogen-resistant breast cancer cells to ICI 182,780 by preventing the anti-apoptotic function of GRP78. (c) 2012 Elsevier Ireland Ltd. All rights reserved.
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