Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer.
The proinflammatory chemokine interleukin-8 (IL-8) is undetectable in androgen-responsive prostate cancer cells (e.g., LNCaP and LAPC-4), but it is highly expressed in androgen-independent metastatic cells, such as PC-3. In this report, we show IL-8 functions in androgen independence, chemoresistance, tumor growth, and angiogenesis. We stably transfected LNCaP and LAPC-4 cells with IL-8 cDNA and selected IL-8-secreting (IL8-S) transfectants. The IL8-S transfectants that secreted IL-8 at levels similar to that secreted by PC-3 cells (100-170 ng/10(6) cells) were characterized. Continuous or transient exposure of LNCaP and LAPC-4 cells to IL-8 reduced their dependence on androgen for growth and decreased sensitivity (>3.5x) to an antiandrogen. IL-8-induced cell proliferation was mediated through CXCR1 and was independent of androgen receptor (AR). Quantitative PCR, immunoblotting, and transfection studies showed that IL8-S cells or IL-8-treated LAPC-4 cells exhibit a 2- to 3-fold reduction in PSA and AR levels, when compared with vector transfectants. IL8-S cells expressed 2- to 3-fold higher levels of phospho-EGFR, src, Akt, and nuclear factor kappaB (NF-kappaB) and showed increased survival when treated with docetaxel. This increase was blocked by NF-kappaB and src inhibitors, but not by an Akt inhibitor. IL8-S transfectants displayed a 3- to 5-fold increased motility, invasion, matrix metalloproteinase-9 and vascular endothelial growth factor production. LNCaP IL8-S cells grew rapidly as tumors, with increased microvessel density and abnormal tumor vasculature when compared with the tumors derived from their vector-transfected counterparts. Therefore, IL-8 is a molecular determinant of androgen-independent prostate cancer growth and progression.
Araki
Shinako
S
Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
Omori
Yohei
Y
Lyn
Dominic
D
Singh
Rajendra K
RK
Meinbach
David M
DM
Sandman
Yekutiel
Y
Lokeshwar
Vinata B
VB
Lokeshwar
Bal L
BL
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry
D000728:Androgens; D016209:Interleukin-8; D016328:NF-kappa B; D011944:Receptors, Androgen; D011994:Recombinant Proteins