TY - JOUR
T1 - Identification of an IL-1-induced gene expression pattern in AR + PCa cells that mimics the molecular phenotype of AR − PCa cells
AU - Thomas-Jardin, Shayna E.
AU - Kanchwala, Mohammed S.
AU - Jacob, Joan
AU - Merchant, Sana
AU - Meade, Rachel K.
AU - Gahnim, Nagham M.
AU - Nawas, Afshan F.
AU - Xing, Chao
AU - Delk, Nikki A.
N1 - Funding Information:
Constantinou (Rice University). We would also like to acknowledge financial support for the Delk lab from the University of Texas at Dallas and financial support from the National Institutes of Health (NIH/NCI R21CA175798 [Delk]; NIH/NCI K01CA160602 [Delk]; NIH UL1TR001105 [Xing]).
Funding Information:
National Cancer Institute, Grant numbers: K01CA160602, R21CA175798; National Institutes of Health, Grant number: UL1TR001105
Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Background: In immunosurveillance, bone-derived immune cells infiltrate the tumor and secrete inflammatory cytokines to destroy cancer cells. However, cancer cells have evolved mechanisms to usurp inflammatory cytokines to promote tumor progression. In particular, the inflammatory cytokine, interleukin-1 (IL-1), is elevated in prostate cancer (PCa) patient tissue and serum, and promotes PCa bone metastasis. IL-1 also represses androgen receptor (AR) accumulation and activity in PCa cells, yet the cells remain viable and tumorigenic; suggesting that IL-1 may also contribute to AR-targeted therapy resistance. Furthermore, IL-1 and AR protein levels negatively correlate in PCa tumor cells. Taken together, we hypothesize that IL-1 reprograms AR positive (AR + ) PCa cells into AR negative (AR − ) PCa cells that co-opt IL-1 signaling to ensure AR-independent survival and tumor progression in the inflammatory tumor microenvironment. Methods: LNCaP and PC3 PCa cells were treated with IL-1β or HS-5 bone marrow stromal cell (BMSC) conditioned medium and analyzed by RNA sequencing and RT-QPCR. To verify genes identified by RNA sequencing, LNCaP, MDA-PCa-2b, PC3, and DU145 PCa cell lines were treated with the IL-1 family members, IL-1α or IL-1β, or exposed to HS-5 BMSC in the presence or absence of Interleukin-1 Receptor Antagonist (IL-1RA). Treated cells were analyzed by western blot and/or RT-QPCR. Results: Comparative analysis of sequencing data from the AR + LNCaP PCa cell line versus the AR − PC3 PCa cell line reveals an IL-1-conferred gene suite in LNCaP cells that is constitutive in PC3 cells. Bioinformatics analysis of the IL-1 regulated gene suite revealed that inflammatory and immune response pathways are primarily elicited; likely facilitating PCa cell survival and tumorigenicity in an inflammatory tumor microenvironment. Conclusions: Our data supports that IL-1 reprograms AR + PCa cells to mimic AR − PCa gene expression patterns that favor AR-targeted treatment resistance and cell survival.
AB - Background: In immunosurveillance, bone-derived immune cells infiltrate the tumor and secrete inflammatory cytokines to destroy cancer cells. However, cancer cells have evolved mechanisms to usurp inflammatory cytokines to promote tumor progression. In particular, the inflammatory cytokine, interleukin-1 (IL-1), is elevated in prostate cancer (PCa) patient tissue and serum, and promotes PCa bone metastasis. IL-1 also represses androgen receptor (AR) accumulation and activity in PCa cells, yet the cells remain viable and tumorigenic; suggesting that IL-1 may also contribute to AR-targeted therapy resistance. Furthermore, IL-1 and AR protein levels negatively correlate in PCa tumor cells. Taken together, we hypothesize that IL-1 reprograms AR positive (AR + ) PCa cells into AR negative (AR − ) PCa cells that co-opt IL-1 signaling to ensure AR-independent survival and tumor progression in the inflammatory tumor microenvironment. Methods: LNCaP and PC3 PCa cells were treated with IL-1β or HS-5 bone marrow stromal cell (BMSC) conditioned medium and analyzed by RNA sequencing and RT-QPCR. To verify genes identified by RNA sequencing, LNCaP, MDA-PCa-2b, PC3, and DU145 PCa cell lines were treated with the IL-1 family members, IL-1α or IL-1β, or exposed to HS-5 BMSC in the presence or absence of Interleukin-1 Receptor Antagonist (IL-1RA). Treated cells were analyzed by western blot and/or RT-QPCR. Results: Comparative analysis of sequencing data from the AR + LNCaP PCa cell line versus the AR − PC3 PCa cell line reveals an IL-1-conferred gene suite in LNCaP cells that is constitutive in PC3 cells. Bioinformatics analysis of the IL-1 regulated gene suite revealed that inflammatory and immune response pathways are primarily elicited; likely facilitating PCa cell survival and tumorigenicity in an inflammatory tumor microenvironment. Conclusions: Our data supports that IL-1 reprograms AR + PCa cells to mimic AR − PCa gene expression patterns that favor AR-targeted treatment resistance and cell survival.
KW - androgen receptor
KW - gene expression pattern
KW - interleukin-1
KW - prostate cancer
KW - treatment resistance
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U2 - 10.1002/pros.23504
DO - 10.1002/pros.23504
M3 - Article
C2 - 29527701
AN - SCOPUS:85045146385
SN - 0270-4137
VL - 78
SP - 595
EP - 606
JO - Prostate
JF - Prostate
IS - 8
ER -