Abstract
IGF-II plays a crucial role in fetal and cancer development by signaling through the IGF-I receptor. We have shown that inhibition of IGF-II by resveratrol (RSV) induced apoptosis and that proIGF-II (highly expressed in cancer) was more potent than mIGF-II in inhibiting this effect. Thus, we hypothesized that IGF-II differentially regulates the signaling cascade of the IGF-I receptor to stimulate the anti-apoptotic proteins Bcl-2 and Bcl-X(L) to prevent apoptosis. RSV treatment to breast cancer cells inhibited Bcl-2 and Bcl-X(L) expression and induced mitochondrial membrane depolarization. ProIGF-II was more potent than mIGF-II in: (1) activating the PI3/Akt pathway, (2) regulating Bcl-2 and Bcl-X(L) expression, and (3) inducing phosphorylation/nuclear translocation of Cyclic AMP-responsive element binding protein. Furthermore, IGF-II differentially regulated the intracellular translocation of Bcl-2 and Bcl-X(L), a critical process in breast cancer progression to hormone-independence. Our study provides a novel mechanism of how proIGF-II promotes progression and chemoresistance in breast cancer development.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Survival / drug effects
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Cytochromes c / metabolism
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Expression Regulation, Neoplastic / physiology*
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Humans
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Insulin-Like Growth Factor II / metabolism
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Insulin-Like Growth Factor II / pharmacology*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mitochondrial Membranes / drug effects
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Phosphorylation / drug effects
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Protein Transport / drug effects
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Resveratrol
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Signal Transduction / drug effects*
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Stilbenes / pharmacology
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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Antineoplastic Agents, Phytogenic
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BCL2L1 protein, human
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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RNA, Small Interfering
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Stilbenes
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bcl-X Protein
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Insulin-Like Growth Factor II
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Cytochromes c
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Resveratrol