MMP9 activation triggered by epidermal growth factor induced FoxO1 nuclear exclusion in non-small cell lung cancer

Tumour Biol. 2014 Jul;35(7):6673-8. doi: 10.1007/s13277-014-1850-z. Epub 2014 Apr 6.

Abstract

The molecular mechanism underlying activation of matrix metallopeptidase 9 (MMP9) in non-small cell lung cancer (NSCLC) cells, which controls cancer invasiveness and metastasis, remains elusive. Here, we reported a strong correlation of epidermal growth factor receptor (EGFR) and MMP9 levels in NSCLC patients. Thus, we used a human NSCLC line, A549, to examine whether there is a causal link between EGFR and MMP9 activation. We found that EGF-induced activation of EGFR in A549 cells activated MMP9, resulting in an increase in cancer invasiveness. An EGFR inhibitor efficiently blocked this EGF-induced activation of MMP9 and, consequently, increased cancer invasiveness. Moreover, an inhibitor for phosphatidylinositol 3-kinase (PI3K)/Akt, but not an inhibitor for mitogen-activated protein kinase, or an inhibitor for Jun N-terminal kinase, significantly inhibited the epidermal growth factor (EGF)-induced activation of MMP9, suggesting that PI3K/Akt signaling cascades may be responsible for EGF-activated MMP9. We further dissected the pathway and found that nuclear exclusion of a major Akt downstream target, FoxO1, occurred by EGF-induced Akt activation, which could be inhibited by either EGFR inhibitor or by PI3K/Akt inhibitor. In a loss of function, expression of a constitutive nuclear form of FoxO1 significantly inhibited MMP9 activation induced by EGF. Taken together, these findings suggest that EGF/EGFR signaling activates downstream PI3K/Akt to induce FoxO1 nuclear exclusion, which activates MMP9 to promote NSCLC invasiveness. Thus, Akt and FoxO1, in addition to the well-known EGFR, appear to be promising therapeutic targets for preventing the metastasis of NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Epidermal Growth Factor / genetics
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / genetics*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Invasiveness / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction

Substances

  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Epidermal Growth Factor
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • MMP9 protein, human
  • Matrix Metalloproteinase 9