Pneumologie 2018; 72(03): 230
DOI: 10.1055/s-0037-1615330
Lungenfibrose
Georg Thieme Verlag KG Stuttgart · New York

Lipopolysaccharides Induce Radiotherapy Resistance in Non-Small Cell Lung Cancer Cell Lines – the Role of Protein Kinase-Activation

MY Gökyildirim
1   Universities of Gießen and Marburg Lung Center (UGMLC) – Gießen/DE
,
FSB Subtil
2   Universities of Gießen and Marburg Lung Center (UGMLC), Philipps-University Marburg – Marburg/DE
,
U Grandel
1   Universities of Gießen and Marburg Lung Center (UGMLC) – Gießen/DE
,
F Grimminger
1   Universities of Gießen and Marburg Lung Center (UGMLC) – Gießen/DE
,
R Engenhart-Cabillic
2   Universities of Gießen and Marburg Lung Center (UGMLC), Philipps-University Marburg – Marburg/DE
,
W Seeger
3   Universities of Gießen and Marburg Lung Center (UGMLC), The German Center for Lung Research (DZL), Germany – Gießen/DE
,
U Sibelius
1   Universities of Gießen and Marburg Lung Center (UGMLC) – Gießen/DE
,
K Hattar
1   Universities of Gießen and Marburg Lung Center (UGMLC) – Gießen/DE
› Author Affiliations
Further Information

Publication History

Publication Date:
07 March 2018 (online)

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Rationale:

Lung cancer is the leading cause of cancer death. Pulmonary infections are common complications in patients with lung cancer and worsen prognosis. These patients often show an acquired resistance to radiotherapy.

Gram-negative bacteria are common pathogens in lung cancer. Their virulence is caused by cell wall components, especially by Lipopolysaccharides (LPS). LPS is known to activate multiple pathways in pulmonary epithelial cells. It has been shown that LPS promotes non-small cell lung cancer (NSCLC) growth in vitro an in vivo. It is not clear whether LPS could induce radiotherapy resistance in NSCLC cells.

Methods:

Colony formation assays were performed to quantify the survival after ionizing irradiation. Human lung cancer cell lines were treated with different concentrations of LPS (0, 0.1, 1 and 10 µg/ml) and exposed to ionizing radiation (0, 1, 2, 4, 6 and 8 Gy). A defined number of treated cells were plated on dishes and after 10 days the colonies were counted. The plating efficiency and the survival rate were calculated.

In parallel, proteome arrays were performed. Up-regulated target proteins were inhibited in LPS-treated cells before irradiation.

Results:

Ionizing radiation induced a reduction in clonogenic survival. However in LPS treated cells the effect of ionizing radiation was severely attenuated; the sensitivity to radiotherapy was remarkably decreased in the human adenocarcinoma cell line H1975. This effect was dose dependent and most pronounced when 10 µg/ml LPS were used. In H1975 cells the survival fraction increased significantly in the presence of LPS.

The proteome array shows an upregulation of the cAMP response element-binding protein (CREB) and EGFR after LPS treatment and radiation. After CREB binding protein (CBP) or EGFR inhibition the LPS-induced resistance to radiotherapy was decreased, meaning sensitivity to irradiation was restored.

Conclusion:

LPS induces radiotherapy resistance by EGFR- and CREB-dependent mechanisms. This means that bacterial infections could directly affect response to radiotherapy in NSCLC.

The LPS treatment of H1975 cells induces radiotherapy resistance. Therefore, inhibition of possible target proteins like CREB or EGFR may serve as a potential treatment to overcome resistance to radiotherapy.