Molecular mechanism of interferon alfa-mediated growth inhibition in human neuroendocrine tumor cells

Gastroenterology. 2000 Apr;118(4):735-48. doi: 10.1016/s0016-5085(00)70143-0.


Background & aims: Although human neuroendocrine tumors respond to interferon (IFN)-alpha treatment in vivo, the underlying mechanisms of growth inhibition are poorly understood. To characterize the antiproliferative effects at a molecular level, we explored the growth-regulatory action of IFN-alpha in the human neuroendocrine tumor cell lines BON and QGP1.

Methods: IFN-alpha receptor expression and signal transduction were examined by reverse-transcription polymerase chain reaction, immunoblotting, subcellular fractionation, and transactivation assays. Growth regulation was evaluated by cell numbers, soft agar assays, and cell cycle analysis using flow cytometry. Expression and activity of cell cycle-regulatory molecules were determined by immunoblotting and histone H1-kinase assays.

Results: Both cell lines expressed IFN-alpha receptor mRNA transcripts. Ligand binding initiated phosphorylation of Jak kinases and Stat transcription factors, resulting in Stat activation, nuclear translocation, and transcription from an ISRE-reporter construct. Prolonged IFN-alpha treatment dose-dependently inhibited both anchorage-dependent and -independent growth. Cell cycle analysis of IFN-alpha-treated, unsynchronized cultures revealed an increased S-phase population, which was further substantiated in G(1) synchronized QGP1 cells. IFN-alpha-treated cells entered S phase in parallel to control cultures, but their progress into G(2)/M phase was delayed. Both cellular cyclin B levels and CDC 2 activity were substantially reduced. The extent and time course of this reduction corresponded to the observed S-phase accumulation.

Conclusions: IFN-alpha directly inhibits growth of human neuroendocrine tumor cells by specifically delaying progression through S phase and into G(2)/M. These cell cycle changes are associated with inhibition of cyclin B expression, resulting in reduced CDC2 activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • CDC2 Protein Kinase / antagonists & inhibitors
  • Cell Division / drug effects
  • Cyclin B / antagonists & inhibitors
  • Humans
  • Interferon-alpha / metabolism
  • Interferon-alpha / pharmacology*
  • Neuroendocrine Tumors / pathology*
  • RNA, Messenger / metabolism
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • S Phase
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Cyclin B
  • Interferon-alpha
  • RNA, Messenger
  • Receptors, Interferon
  • CDC2 Protein Kinase