Fractionated Radiation Therapy Can Induce a Molecular Profile for Therapeutic Targeting

John-Aryankalayil, Molykutty; Palayoor, Sanjeewani T.; Cerna, David; Simone, Charles B.; Falduto, Michael T.; Magnuson, Scott R.; Coleman, C. Norman

doi:10.1667/rr2105.1

Cited by 49 publications

(66 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results were recently confirmed for breast, glioma, and prostate cancer cell lines (18,19) and indicate that ionizing radiation leads to the induction of the IFN/Stat1 pathway in tumor cells. STAT1 seems to have a dominant role in the expression of IRDS genes.…”

Section: Clinical-translational Advancesmentioning

confidence: 57%

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

Khodarev

Roizman²,

Weichselbaum³

2012

Clinical Cancer Research

164

167

View full text Add to dashboard Cite

STAT1 is activated by IFNs and other cell signals. Following activation, STAT1 is translocated to the nuclei and activates transcription of IFN-stimulated genes. Although the activation of STAT1 by IFNs is classically associated with antiviral defense and tumor-suppressive functions, emerging data indicate that expression of the STAT1 pathway confers cellular resistance to DNA-damaging agents and mediates aggressive tumor growth. Recent advances in the development of Janus-activated kinase/Stat inhibitors and peptide inhibitors specific for individual Stat proteins may provide new insights into the controversial functions of this pathway. Clin Cancer Res; 18(11); 3015-21. Ó2012 AACR.

show abstract

Section: Clinical-translational Advancesmentioning

confidence: 57%

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

Khodarev

Roizman²,

Weichselbaum³

2012

Clinical Cancer Research

164

167

View full text Add to dashboard Cite

show abstract

“…Previous studies from our group demonstrated that the PC3 prostate carcinoma cell line showed a significant upregulation of immune-related genes after multifractionated treatment (12), suggesting that radiation therapy has the potential to elicit an immune response that will initiate a cascade of events leading to immunogenic antitumor effects. Corroborating evidence based on gene expression studies in prostate and breast cancers exhibited a distinctive upregulation of interferon-related genes after multifractionated therapy when compared to single-dose treatment (13).…”

Section: Introductionmentioning

confidence: 96%

Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells

et al. 2014

Self Cite

View full text Add to dashboard Cite

To understand the impact of clinically relevant radiation therapy (RT) on tumor immune gene expression and to utilize the changes that occur during treatment to improve cancer treatment outcome, we examined how immune response genes are modulated in prostate cancer cells of varying p53 status. LNCaP (p53 wild-type), PC3 (p53 null) and DU145 (p53 mutant) cells received a 10 Gy single dose or 1 Gy × 10 multifractionated radiation dose to simulate hypofractionated and conventionally fractionated prostate radiotherapy. Total RNA was isolated 24 h after multi-fractionated radiation treatment and single-dose treatments and subjected to microarray analysis and later validated by RT-PCR. RT-PCR was utilized to identify total-dose inflection points for significantly upregulated genes in response to multifractionated radiation therapy. Radiation-induced damage-associated molecular pattern molecules (DAMPs) and cytokine analyses were performed using bioluminescence and ELISA. Multifractionated doses activated immune response genes more robustly than single-dose treatment, with a relatively larger number of immune genes upregulated in PC3 compared to DU145 and LNCaP cells. The inflection point of multifractionated radiation-induced immune genes in PC3 cells was observed in the range of 8–10 Gy total radiation dose. Although both multifractionated and single-dose radiation-induced proinflammatory DAMPs and positively modulated the cytokine environment, the changes were of higher magnitude with multifractionated therapy. The findings of this study together with the gene expression data suggest that cells subjected to multifractionated radiation treatment would promote productive immune cell–tumor cell interactions.

show abstract

“…innate immunity | cytoplasmic sensor | interferon beta | DHX58 S everal studies have shown that the response of tumor cells to ionizing radiation (IR) is associated with IFN-mediated signaling (1)(2)(3)(4)(5)(6). IFN signaling leads to the induction of multiple IFN stimulated genes (ISGs) (7,8) and activates growth arrest and cell death in exposed cell populations (9).…”

mentioning

confidence: 99%

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

Widau¹,

Parekh²,

Ranck³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.innate immunity | cytoplasmic sensor | interferon beta | DHX58

show abstract

Fractionated Radiation Therapy Can Induce a Molecular Profile for Therapeutic Targeting

Cited by 49 publications

References 41 publications

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

Contact Info

Product

Resources

About