Metabolic dependence of cyclosporine A on cell proliferation of human non‑small cell lung cancer A549 cells and its implication in post‑transplant malignancy

Qin,Xinghua; Chen,Ziwei

doi:10.3892/or.2019.7076

Metabolic dependence of cyclosporine A on cell proliferation of human non‑small cell lung cancer A549 cells and its implication in post‑transplant malignancy

Authors:
- Xinghua Qin
- Ziwei Chen
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Affiliations: School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, P.R. China, Research Center for Prevention and Treatment of Respiratory Disease, School of Clinical Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
Published online on: March 18, 2019 https://doi.org/10.3892/or.2019.7076
Pages: 2997-3004

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Abstract

Cyclosporine A (CsA), a widely used immunosuppressant to prevent organ transplant rejection, is associated with an increased cancer risk following transplantation, particularly in the lung. However, the underlying mechanisms remain unclear. In the present study, using human non‑small cell lung cancer A549 cells, it was determined that CsA (0.1 or 1 µM) promoted cell proliferation with glucose alone as the energy source. CsA treatment increased the phosphorylation of protein kinase B (Akt) and consequently the expression of Cyclin D1. Inhibiting Akt signaling with the phosphatidylinositol 3‑kinase inhibitor wortmannin prevented this effect. Mechanistically, CsA treatment increased reactive oxygen species (ROS) generation, and the intracellular ROS scavenger N‑acetyl‑cysteine (NAC) attenuated CsA‑induced cell proliferation as well as the activation of Akt/Cyclin D1 signaling. However, notably, it was demonstrated that CsA treatment decreased cell proliferation and Akt phosphorylation under normal lipid loading. Further investigation indicated that palmitic acid induced excessive generation of ROS, while CsA treatment further stimulated this ROS production. Scavenging intracellular ROS with NAC attenuated the CsA‑mediated inhibition of cell proliferation. Collectively, the results indicated a pleiotropic effect of CsA in the regulation of A549 cell proliferation under different metabolic conditions. This indicated that CsA administration may contribute to increased post‑transplant cancer risk in organ recipients.

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