Interleukin-8 signaling promotes translational regulation of cyclin D in androgen-independent prostate cancer cells.
We have shown previously that interleukin-8 (IL-8) and IL-8 receptor expression is elevated in tumor cells of human prostate biopsy tissue and correlates with increased cyclin D1 expression. Using PC3 and DU145 cell lines, we sought to determine whether IL-8 signaling regulated cyclin D1 expression in androgen-independent prostate cancer (AIPC) cells and to characterize the signaling pathways underpinning this response and that of IL-8-promoted proliferation. Administration of recombinant human IL-8 induced a rapid, time-dependent increase in cyclin D1 expression in AIPC cells, a response attenuated by the translation inhibitor cycloheximide but not by the RNA synthesis inhibitor, actinomycin D. Suppression of endogenous IL-8 signaling using neutralizing antibodies to IL-8 or its receptors also attenuated basal cyclin D1 expression in AIPC cells. Immunoblotting using phospho-specific antibodies confirmed that recombinant human IL-8 induced rapid time-dependent phosphorylation of Akt and the mammalian target of rapamycin substrate proteins, 4E-BP1 and ribosomal S6 kinase, resulting in a downstream phosphorylation of the ribosomal S6 protein (rS6). LY294002 and rapamycin each abrogated the IL-8-promoted phosphorylation of rS6 and attenuated the rate of AIPC cell proliferation. Our results indicate that IL-8 signaling (a) regulates cyclin D1 expression at the level of translation, (b) regulates the activation of proteins associated with the translation of capped and 5'-oligopyrimidine tract transcripts, and (c) activates signal transduction pathways underpinning AIPC cell proliferation. This study provides a molecular basis to support the correlation of IL-8 expression with that of cyclin D1 in human prostate cancer and suggests a mechanism by which this chemokine promotes cell proliferation.
MacManus
Christopher F
CF
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast City Hospital, University Floor, Lisburn Road, Belfast BT9 7AB, Northern Ireland.
Pettigrew
Johanna
J
Seaton
Angela
A
Wilson
Catherine
C
Maxwell
Pamela J
PJ
Berlingeri
Silvia
S
Purcell
Colin
C
McGurk
Maryalice
M
Johnston
Patrick G
PG
Waugh
David J J
DJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000728:Androgens / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D000728:Androgens; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D016209:Interleukin-8; D019869:Phosphatidylinositol 3-Kinases; D010739:Phospholipase D; D010750:Phosphoproteins; D011493:Protein Kinase C; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human; C546842:MTOR protein, human; C115015:PKC-3 protein