Abstract
Recent studies have suggested that 5-aminosalicylic acid (5-ASA) inhibits colorectal cancer (CRC) development. However, the mechanism underlying the antineoplastic effect of 5-ASA remains unknown. We here examined the effect of 5-ASA on epidermal growth factor receptor (EGFR) activation, a pathway that triggers mitogenic signals in CRC cells. We show that 5-ASA inhibits EGFR activation, through a mechanism that does not rely on CRC cell death induction. 5-ASA enhances the activity, but not expression, of phosphorylated (p)-EGFR-targeting phosphatases (PTPs), and treatment of cells with PTP inhibitors abrogates the 5-ASA-mediated EGFR dephosphorylation. Both SH-PTP1 and SH-PTP2 interact with EGFR upon 5-ASA treatment. However, knockdown of SH-PTP2 but not SH-PTP1 by small interference RNAs prevents the 5-ASA-induced EGFR dephosphorylation. Finally, we show that 5-ASA attenuates p-EGFR in ex vivo organ cultures of CRC explants. Data indicate that 5-ASA disrupts EGFR signalling by enhancing SH-PTP2 activity, and suggest a mechanism by which 5-ASA interferes with CRC growth.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / enzymology
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Adenocarcinoma / genetics
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Adenocarcinoma / physiopathology*
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Apoptosis / drug effects
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Apoptosis / physiology
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colorectal Neoplasms / enzymology
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / physiopathology*
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Enzyme Activation
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ErbB Receptors / drug effects
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ErbB Receptors / metabolism*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins / physiology
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Male
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Mesalamine / pharmacology*
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Protein Tyrosine Phosphatases / physiology
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RNA Interference
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RNA, Small Interfering / pharmacology
Substances
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Intracellular Signaling Peptides and Proteins
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RNA, Small Interfering
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Mesalamine
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ErbB Receptors
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases