XPC inhibition rescues cisplatin resistance via the Akt/mTOR signaling pathway in A549/DDP lung adenocarcinoma cells.

Abstract

Xeroderma pigmentosum, complementation group C (XPC) is an accessory recognition gene involved in the nucleotide excision repair (NER) pathway, which is activated during the initial DNA damage recognition stage. It participates in the regulation of DNA damage‑induced proliferation and apoptosis. Emerging evidence demonstrates that upregulation of XPC increases the resistance of several tumor cell types to cytotoxic drugs. In addition, it can predict poor patient outcome for non‑small cell lung cancer (NSCLC). However, the mechanisms linking upregulation of XPC and drug resistance in lung cancer are still unclear. In the present study, we aimed to confirm whether XPC was involved in the reversal of the cisplatin (DDP) resistance in drug‑resistant A549/DDP lung adenocarcinoma cells. RT‑PCR and western blot assays were used to examine XPC mRNA and protein expression levels. Cell viability was assessed by CCK‑8 assay. The knockdown of XPC was achieved in A549/DDP cells using si‑RNA, whereas cell proliferation and apoptosis were assessed by wound healing assay and flow cytometric analysis, respectively. The median inhibitory concentration (IC50) value of DDP was assessed by CCK‑8 assay. Western blot assays were conducted for the examination of caspase‑9/3, Bax and Bcl‑2 protein levels, whereas the activation of the PI3K/Akt/mTOR signaling pathway was investigated in XPC‑knockdown cells. High expression of XPC was noted in A549/DDP cells compared with that in A549 cells, which was associated with DDP resistance. XPC silencing significantly inhibited A549/DDP cell proliferation and increased the induction of apoptosis. In addition, XPC knockdown decreased the expression levels of the Akt/mTOR signaling proteins and the expression of their downstream mediator. The data of the present study revealed that XPC inhibition rescued DDP resistance in lung adenocarcinoma cells, which was dependent on the Akt/mTOR signaling pathway. Collectively, XPC may be considered a new strategy for curing DDP‑resistant lung cancer and may improve the efficacy of conventional chemotherapy.

• Authors: Xue Teng, Xiao-Fan Fan, Qi Li, Shuang Liu, Dong-Yuan Wu, Shu-Ya Wang, Yuanqi Shi, Mei Dong
• Journal: Oncology reports (Oncol Rep) Vol. 41 Issue 3 Pg. 1875-1882 (Mar 2019) ISSN: 1791-2431 [Electronic] Greece
• PMID: 30628719 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• RNA, Messenger
• RNA, Small Interfering
• XPC protein, human
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Cisplatin

Topics

• A549 Cells
• Adenocarcinoma of Lung (drug therapy, genetics, pathology)
• Apoptosis (drug effects, genetics)
• Cell Proliferation (drug effects, genetics)
• Cisplatin (pharmacology, therapeutic use)
• DNA Damage (drug effects)
• DNA Repair (genetics)
• DNA-Binding Proteins (genetics, metabolism)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Inhibitory Concentration 50
• Lung Neoplasms (drug therapy, genetics, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (metabolism)
• RNA, Small Interfering (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Up-Regulation