Role of the protein tyrosine phosphatase SHP-1 in Interleukin-6 regulation of prostate cancer cells.
BACKGROUND
Interleukin-6 (IL-6) is a multifunctional cytokine that has been implicated in the modulation of growth and progression of prostate cancer. Decreased expression of the tyrosine phosphatase SHP-1, involved in regulation of cytokine and tyrosine kinase receptor signaling, has been shown to be associated with less favorable outcome among prostate cancer patients.


METHODS
Parental LNCaP cells and an LNCaP-IL6+ subline, derived from parental LNCaP cells by continuous culture of the cells in the presence of recombinant IL-6 were used in the study. Expression of STAT3, pSTAT3, ERK, pERK, AKT, pAKT, PTEN, and SHP-1 was analyzed by immunohistochemistry, Western blots, cDNA microarray, quantitative PCRs, and reverse transcriptase PCRs. Proliferation and apoptosis of transfected cells were analyzed by caspase3/7 assay and flow cytometry.


RESULTS
Phosphorylation of ERK and STAT3 was increased in the LNCaP-IL6+ subline compared with LNCaP cells, whereas pAKT was decreased. Overexpression and inhibition experiments with SHP-1 siRNA showed that SHP-1 reduced proliferation and increased apoptosis in both cell lines. Microarray analysis revealed 80 up-regulated and 87 down-regulated SHP-1-related genes in the LNCaP-IL6+ cell line compared with LNCaP cells.


CONCLUSIONS
SHP-1 suppresses growth and increases apoptosis in both LNCaP and LNCaP-IL6+ cells, which suggests that SHP-1 could be a therapeutic target in prostate cancer, even when there is an IL-6-related growth advantage.
Tassidis
Helena
H
Department of Laboratory Medicin, Tumour Biology, Lund University, Malmö University Hospital, Malmö, Sweden. helena.tassidis@med.lu.se
Culig
Zoran
Z
Wingren
Anette Gjörloff
AG
Härkönen
Pirkko
P
D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D015850:Interleukin-6 / Q000502:physiology*; D007700:Kinetics; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation
D017931:DNA Primers; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053148:Caspase 3; D053179:Caspase 7