Interferon-gamma-mediated growth regulation of melanoma cells: involvement of STAT1-dependent and STAT1-independent signals

J Invest Dermatol. 2004 Feb;122(2):414-22. doi: 10.1046/j.0022-202X.2004.22237.x.


Interferon-gamma, a known inhibitor of tumor cell growth, has been used in several protocols for the treatment of melanoma. We have studied the molecular events underlying interferon-gamma-induced G0/G1 arrest in four metastatic melanoma cell lines with different responsiveness to interferon-gamma. The growth arrest did not result from enhanced expression of cyclin-dependent kinase inhibitors p21 and p27. Instead, it correlated with downregulation of cyclin E and cyclin A and inhibition of their associated kinase activities. We show that interferon-gamma-induced growth inhibition could be abrogated by overexpression of dominant negative STAT1 (signal transducer and activator of transcription 1) in the melanoma cell line A375, suggesting that STAT1 plays a crucial part for the anti-proliferative effect. Erythropoietin stimulation of a chimeric receptor led to a concentration-dependent STAT1 activation and concomitant growth arrest when it contained the STAT recruitment motif Y440 of the interferon-gamma receptor 1. In contrast, dose-response studies for interferon-gamma revealed a discrepancy between levels of STAT1 activation and the extent of growth inhibition; whereas STAT1 was activated by low doses of interferon-gamma (10 U per mL), growth inhibitory effects were only visible with 100-fold higher concentrations. Our results suggest the presence of additional signals emanating from the interferon-gamma receptor, which may counteract the anti-proliferative function of STAT1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor / cytology
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm
  • G1 Phase / drug effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferon-gamma / pharmacology*
  • Melanoma*
  • Resting Phase, Cell Cycle / drug effects
  • STAT1 Transcription Factor
  • Signal Transduction / drug effects
  • Skin Neoplasms*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*


  • Antineoplastic Agents
  • Cyclins
  • DNA-Binding Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Interferon-gamma
  • Cyclin-Dependent Kinases