Abstract
SRC-3/AIB1 (steroid receptor coactivator 3/amplified in breast cancer 1) is an authentic oncogene that contributes to the development of drug resistance and poor disease-free survival in cancer patients. Autophagy is also an important cell death mechanism that has tumor suppressor function. In this study, we identified macrophage migration inhibitory factor (MIF) as a novel target gene of SRC-3 and demonstrated its importance in cell survival. Specifically, we showed that MIF is a strong suppressor of autophagic cell death. We further showed that suppression of MIF, in turn, induced autophagic cell death, enhanced chemosensitivity and inhibited tumorigenesis in a xenograft mouse tumorigenesis model. Our study demonstrated that regulation of MIF expression and suppression of autophagic cell death is a potent mechanism by which SRC-3 contributes to increased chemoresistance and tumorigenicity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Hypoxia
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Cell Line, Tumor
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Cell Survival
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Female
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HEK293 Cells
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HeLa Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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I-kappa B Kinase / metabolism
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Macrophage Migration-Inhibitory Factors / antagonists & inhibitors
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Macrophage Migration-Inhibitory Factors / genetics
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Macrophage Migration-Inhibitory Factors / metabolism*
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Mice
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Nuclear Receptor Coactivator 3 / antagonists & inhibitors
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Nuclear Receptor Coactivator 3 / genetics
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Nuclear Receptor Coactivator 3 / metabolism*
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Peptide Fragments / metabolism
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Phosphorylation
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Promoter Regions, Genetic
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RNA Interference
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / therapeutic use
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Sialoglycoproteins / metabolism
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Transplantation, Heterologous
Substances
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Hypoxia-Inducible Factor 1, alpha Subunit
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Macrophage Migration-Inhibitory Factors
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Peptide Fragments
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RNA, Small Interfering
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Sialoglycoproteins
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bone sialoprotein (35-62), human
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Nuclear Receptor Coactivator 3
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I-kappa B Kinase