Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma
Authors
Armstrong, C. W. D.Coulter, J. A.
Ong, C. W.
Maxwell, P. J.
Walker, S.
Butterworth, K. T.
Lyubomska, O.
Berlingeri, S.
Gallagher, R.
O'Sullivan, J. M.
Jain, S.
Mills, I. G.
Prise, K. M.
Bristow, Robert G
LaBonte, M. J.
Waugh, D. J. J.
Affiliation
Movember FASTMAN Centre of Excellence, Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.Issue Date
2020
Metadata
Show full item recordAbstract
Functional impairment of the tumour suppressor PTEN is common in primary prostate cancer and has been linked to relapse post-radiotherapy (post-RT). Pre-clinical modelling supports elevated CXC chemokine signalling as a critical mediator of PTEN-depleted disease progression and therapeutic resistance. We assessed the correlation of PTEN deficiency with CXC chemokine signalling and its association with clinical outcomes. Gene expression analysis characterized a PTEN LOW/CXCR1HIGH/CXCR2HIGH cluster of tumours that associates with earlier time to biochemical recurrence [hazard ratio (HR) 5.87 and 2.65, respectively] and development of systemic metastasis (HR 3.51). In vitro, CXCL signalling was further amplified following exposure of PTEN-deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2 signalling in PTEN-depleted cell-based models increased IR sensitivity. In vivo, administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), or CXCR2-specific antagonist (AZD5069), in combination with IR to PTEN-deficient xenografts attenuated tumour growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 administration attenuated IR-induced CXCL signalling and anti-apoptotic protein expression. Interventions targeting CXC chemokine signalling may provide an effective strategy to combine with RT in locally advanced prostate cancer patients with known presence of PTEN-deficient foci.Citation
Armstrong CWD, Coulter JA, Ong CW, Maxwell PJ, Walker S, Butterworth KT, et al. Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma. NAR Cancer. 2020;2(3):zcaa012.Journal
NAR CancerDOI
10.1093/narcan/zcaa012PubMed ID
32743555Additional Links
https://dx.doi.org/10.1093/narcan/zcaa012Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1093/narcan/zcaa012
Scopus Count
Collections
Related articles
- Potentiation of inflammatory CXCL8 signalling sustains cell survival in PTEN-deficient prostate carcinoma.
- Authors: Maxwell PJ, Coulter J, Walker SM, McKechnie M, Neisen J, McCabe N, Kennedy RD, Salto-Tellez M, Albanese C, Waugh DJ
- Issue date: 2013 Aug
- Interleukin-8 promotes cell migration via CXCR1 and CXCR2 in liver cancer.
- Authors: Bi H, Zhang Y, Wang S, Fang W, He W, Yin L, Xue Y, Cheng Z, Yang M, Shen J
- Issue date: 2019 Oct
- Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells.
- Authors: Maxwell PJ, Neisen J, Messenger J, Waugh DJ
- Issue date: 2014 Jul 15
- ATM Kinase Inhibition Preferentially Sensitises PTEN-Deficient Prostate Tumour Cells to Ionising Radiation.
- Authors: Hanna C, Dunne VL, Walker SM, Butterworth KT, McCabe N, Waugh DJJ, Kennedy RD, Prise KM
- Issue date: 2020 Dec 30
- Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models.
- Authors: Horn LA, Lind H, Fousek K, Qin H, Rajabian N, Angstadt S, Hsiao-Sanchez N, Medina-Enriquez MM, Kelly MD, Allen CT, Hammoudeh SM, Weigert R, Maeda DY, Zebala JA, Palena C
- Issue date: 2024 Dec 5