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Apoptosis

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Fibroblasts from patients with idiopathic pulmonary fibrosis are resistant to cisplatin-induced cell death via enhanced CK2-dependent XRCC1 activity

  • Jintaek Im
  • Richard Seonghun NhoEmail author
Article

Abstract

Idiopathic pulmonary fibrosis (IPF) is a deadly and progressive fibrotic lung disease, but the precise etiology remains elusive. IPF is characterized by the presence of apoptosis-resistant (myo)fibroblasts that relentlessly produce a collagen-rich extracellular matrix (ECM). Recent studies showed that an anti-cancer chemotherapy drug cisplatin is implicated in the development of pulmonary fibrosis, suggesting that the treatment of cancer patients with cisplatin may alter fibroblast viability. To address this possibility, we investigated the cisplatin-induced cell death mechanism in lung fibroblasts derived from IPF and non-IPF patients in response to a collagen matrix. IPF fibroblasts showed enhanced resistance to cisplatin-induced cell death compared to non-IPF fibroblasts in a time- and dose-dependent manner. Molecular study showed that the expression of γH2AX, PUMA and caspase-3/7 activity was abnormally reduced in IPF fibroblasts, suggesting that DNA damage-induced apoptosis caused by cisplatin was suppressed in IPF fibroblasts. Our study further revealed that DNA repair protein XRCC1 activity was aberrantly increased as a result of CK2 hyper-activation in cisplatin-treated IPF fibroblasts, and this alteration protected IPF fibroblasts from cisplatin-induced cell death. Our results showed that IPF fibroblasts residing in a collagen rich matrix are resistance to cisplatin-induced cell death due to the aberrantly high CK2/XRCC1-dependent DNA repair activity. This finding suggests that pulmonary fibrosis may develop and worsen due to the presence of apoptosis-resistant lung fibroblasts in cisplatin-treated cancer patients.

Keywords

IPF Apoptosis Cisplatin Lung fibroblasts 

Notes

Authors’ contribution

JI and RSN participated in the study design and data analysis. JI performed experiments. JI and RSN wrote the manuscript.

Funding

This study was supported by the NHLBI HL114662, University of Minnesota Foundation (UMF) Medical School Faculty Research Award and Center for Lung Science and Health (CLSH) grant (to RSN).

Compliance with ethical standards

Disclosures

Authors declare no competing financial interests.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of MedicineUniversity of MinnesotaMinneapolisUSA

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