Mesothelin-induced pancreatic cancer cell proliferation involves alteration of cyclin E via activation of signal transducer and activator of transcription protein 3

Mol Cancer Res. 2008 Nov;6(11):1755-65. doi: 10.1158/1541-7786.MCR-08-0095.

Abstract

Mesothelin (MSLN) is a cell surface glycoprotein that is overexpressed in human pancreatic cancer. Although its value as a tumor marker for diagnosis and prognosis and as a preferred target of immunointervention has been evaluated, there is little information on the growth advantage of MSLN on tumor cells. In this study, we examined the effect of MSLN on pancreatic cancer cell proliferation, cell cycle progression, expression of cell cycle regulatory proteins, and signal transduction pathways in two pancreatic cancer cell lines, MIA-MSLN (overexpressing MSLN in MIA PaCa-2 cells) and BxPC-siMSLN (silencing MSLN in BxPC-3 cells). Increased cyclin E and cyclin-dependent kinase 2 expression found in MIA-MSLN cells correlated with significantly increased cell proliferation and faster cell cycle progression compared with control cells. BxPC-siMSLN cells showed slower proliferation and slower entry into the S phase than control cells. Signal transducer and activator of transcription protein 3 (Stat3) was constitutively activated in MIA-MSLN cells, but not in control cells. Inhibition of Stat3 activation in MIA-MSLN cells by the Janus-activated kinase-selective inhibitor tyrphostin AG490 was followed by a marked decrease in proliferation of the cells. Small interfering RNA against Stat3 significantly reduced the MIA-MSLN cell cycle progression with a concomitant decrease in cyclin E expression. Our data indicate that overexpression of MSLN in pancreatic cancer cells leads to constitutive activation of the transcription factor Stat3, which results in enhanced expression of cyclin E and cyclin E/cyclin-dependent kinase 2 complex formation as well as increased G(1)-S transition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cyclin E / metabolism*
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Enzyme Inhibitors / pharmacology
  • GPI-Linked Proteins
  • Gene Silencing
  • Humans
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • RNA, Small Interfering / pharmacology
  • S Phase
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Tyrphostins / pharmacology

Substances

  • Antineoplastic Agents
  • Cyclin E
  • Enzyme Inhibitors
  • GPI-Linked Proteins
  • Membrane Glycoproteins
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Janus Kinases
  • Cyclin-Dependent Kinase 2
  • mesothelin