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      Interacting post-muscarinic receptor signaling pathways potentiate matrix metalloproteinase-1 expression and invasion of human colon cancer cells

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          Abstract

          M3 muscarinic receptor (M3R) expression is increased in colon cancer; M3R activation stimulates colon cancer cell invasion via cross-talk with epidermal growth factor receptors (EGFR), post-EGFR activation of mitogen-activated protein kinase (MAPK) ERK1/2, and induction of matrix metalloproteinase-1 ( MMP1) expression. MMP1 expression is strongly associated with tumor metastasis and adverse outcomes. Here, we asked whether other MAPKs regulate M3R agonist-induced MMP1 expression. In addition to activating ERK1/2, we found that treating colon cancer cells with acetylcholine (ACh) stimulated robust time- and dose-dependent phosphorylation of p38 MAPK. Unlike ERK1/2 activation, ACh-induced p38 phosphorylation was EGFR-independent and blocked by inhibiting protein kinase C-α (PKC-α). Inhibiting activation of PKC-α, EGFR, ERK1/2, or p38-α/β alone attenuated but did not abolish ACh-induced MMP1 expression, a finding that predicted potentiating interactions between these pathways. Indeed, ACh-induced MMP1 expression was abolished by incubating cells with either an EGFR or MEK/ERK1/2 inhibitor combined with a p38-α/β inhibitor. Activating PKC-α and EGFR directly with the combination of phorbol 12-myristate 13-acetate (PMA) and EGF potentiated MMP1 gene and protein expression, and cell invasion. PMA- and ACh-induced MMP1 expression were strongly diminished by inhibiting Src and abolished by concurrently inhibiting both p38-α/β and Src, indicating that Src mediates the cross-talk between PKC-α and EGFR signaling. Using siRNA knockdown, we identified p38-α as the relevant p38 isoform. Collectively, these studies uncover novel functional interactions between post-muscarinic receptor signaling pathways that augment MMP1 expression and drive colon cancer cell invasion; targeting these potentiating interactions has therapeutic potential.

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          Author and article information

          Journal
          2984726R
          1011
          Biochem J
          Biochem. J.
          The Biochemical journal
          0264-6021
          1470-8728
          5 October 2017
          20 February 2017
          20 February 2017
          20 February 2018
          : 474
          : 5
          : 647-665
          Affiliations
          []Division of Gastroenterology & Hepatology, Department of Medicine
          [§ ]Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine
          []Veterans Affairs Maryland Health Care System, Baltimore, Maryland 21201-1595
          Author notes
          To whom correspondence should be addressed: Jean-Pierre Raufman, MD, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, 22 South Greene Street, N3W62, Baltimore, MD 21201-1595. Tel: (410) 328-8728; Fax: (410) 328-8315; jraufman@ 123456medicine.umaryland.edu
          [*]

          These authors contributed equally to this work.

          Article
          PMC5650067 PMC5650067 5650067 nihpa910417
          10.1042/BCJ20160704
          5650067
          28008134
          44f821f0-ba79-4ba6-93a4-5989e33676f7
          History
          Categories
          Article

          muscarinic receptors,Matrix metalloproteinases,colorectal cancer,p38 MAPK,cell invasion,cell signaling

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