Differential protein synthesis and expression levels in normal and neoplastic human prostate cells and their regulation by type I and II interferons.
Protein expression and de novo synthesis in normal and prostate cancer cell lines derived from the same patient were compared by proteomic analysis, and the effects of INFalpha and INFgamma (INF=interferon) determined. The expressions of several INF-inducible proteins, including MxA, Nmi, PA28a and IFP53, were downregulated in the cancer cells. INFgamma induced a more than twofold increase or decrease in the synthesis rates of almost twice as many proteins in the cancer cell line. The positive regulator of INF-induced transcription ISGF3gamma was upregulated in the cancer cells and inversely regulated by INFalpha and INFgamma in the normal and cancer cells. Moreover, ISGF3gamma's induction by INFgamma in the cancer cells was more enhanced by simultaneous stimulation with EGF, than its induction in the normal cells. In all, 31 differentially regulated proteins were identified by mass spectrometry analysis, several of which are involved in chaperone-assisted protein folding in the endoplasmic reticulum (ER) or in regulated protein degradation. Our results suggest that the exclusion of proteins by the ER quality control system, crosstalk between the EGF- and INF-induced signalling pathways and the regulation of INF-inducible genes are all altered in the prostate cancer cells. The combination of upregulated activity in the growth-promoting PI3K/Akt pathway, suppression of Nmi and overexpression of hnRNP-K and c-myc proteins may explain why the prostate cancer cells were found to be more resistant to the growth inhibitory effects of INFgamma.
Nagano
Kohji
K
Ludwig Institute for Cancer Research, Royal Free and University College London Medical School, London, UK.
Masters
John R
JR
Akpan
Akunna
A
Yang
Alice
A
Corless
Steve
S
Wood
Chris
C
Hastie
Claire
C
Zvelebil
Marketa
M
Cramer
Rainer
R
Naaby-Hansen
Soren
S
D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015180:Electrophoresis, Gel, Two-Dimensional; D004815:Epidermal Growth Factor / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000096:biosynthesis; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011467:Prostate / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020543:Proteome / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014157:Transcription Factors / Q000096:biosynthesis
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; C099927:NMI protein, human; D020543:Proteome; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins