STAT5 contributes to antiapoptosis in melanoma.
Malignant melanoma is a cancer whose incidence is rising rapidly. Extensive studies of primary tumors and tumor-derived cell lines revealed that inappropriate activation of signal transducer and activator of transcription (STAT) proteins, particularly of STAT3 and 5, occurs with high frequency in various human cancers. We reported that in the Xiphophorus fish melanoma model, constitutive activation of STAT5 correlates with the aggressiveness of melanoma. Investigations in human melanoma mainly focussed on the function of STAT1, but we have shown recently that STAT5 is also activated in human melanoma. The objectives of this investigation were to get more information about the function of STAT5 in melanoma. Here we demonstrate that in murine melanocytes activation of STAT5 measured by its tyrosine phosphorylation and translocation to the nucleus parallels upregulation with its target gene bcl-XL. This indicates a role for STAT5 in antiapoptotic signaling in pigment cells. In human melanoma cell lines, we found that constitutive activation of STAT5 correlates with expression of bcl-XL. Expression of dominant negative STAT5 in the human melanoma cell line A375 leads to a reduced bcl-XL expression and a dramatic increase of apoptotic cells. In contrast to STAT1, which is known to transduce antiproliferative effects of interferons, our data support a significant role for STAT5 in melanoma cell proliferation and survival via the activation of the antiapoptotic protein bcl-XL. Keeping in mind that interferons activate both STAT proteins, STAT5 activation could be of importance in interferon resistance of melanoma.
Hassel
Jessica C
JC
Department of Physiological Chemistry I, Biocenter Theodor Boveri Institute, University of Würzburg, Am Hubland, Würzburg, Germany. j.hassel@dkfz.de
Winnemöller
Dirk
D
Schartl
Manfred
M
Wellbrock
Claudia
C
D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D051020:bcl-X Protein / Q000378:metabolism*
D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; C097276:CILK1 protein, human; D017346:Protein Serine-Threonine Kinases