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Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation-resistant pancreatic cancer

ABSTRACT: Pancreatic cancer (PaCa) has one of the poorest prognoses among gastrointestinal cancers because of rapid development of treatment resistance, which renders chemotherapy and radiotherapy no longer effective. As the mechanism by which PaCa becomes resistant to radiotherapy is unknown, we established radiation-resistant PaCa cell lines to investigate the factors involved in radiation resistance. We investigated the role of the C-X-C motif chemokine 12 (CXCL12)/ C-X-C chemokine receptor type 4 (CXCR4) axis in radiation resistance in PaCa and the effect of a CXCR4 antagonist on radiation-resistant PaCa cell lines. As confirmed by immunofluorescence staining, RT-qPCR, and Western blotting, the expression of CXCR4 was higher in the radiation-resistant PaCa cell lines than in normal PaCa cell lines. The invasion ability of radiation-resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and co-culture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070. Irradiation after treatment with the CXCR4 antagonist suppressed the colonization of radiation-resistant PaCa cell lines. In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. We believe this result will help develop treatments for PaCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193616 | GEO | 2022/01/14

REPOSITORIES: GEO

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Project description:Nathaniel L. Coggins, Danielle Trakimas, S. Laura Chang, Anna Ehrlich, Paramita Ray, Kathryn E. Luker, Jennifer J. Linderman & Gary D. Luker. CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE 9, 6 (2014). Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein β-arrestin 2. Differences in CXCL12-dependent recruitment of β-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of β-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with β-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with β-arrestin 2 and exhibit more gradual, prolonged recruitment of β-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with β-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of β-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of β-arrestin 2 to CXCR7. In silico experiments also identified β-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the "competition" with CXCR4 for CXCL12 and recruitment of β-arrestin 2. These results reveal how competition for β-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.

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Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation-resistant pancreatic cancer

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