Abstract
AimsRadiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance remains to be the major clinic problem for lung cancer patients. Lysimachia capillipes capilliposide C (LC-C), an extract from LC Hemsl, has demonstrated multiple anti-cancer effects in several types of cancer. Here, we investigated the potential therapeutic impacts of LC-C on radiosensitivity in lung cancer cells and their underlying mechanisms.MethodsNon-small cell lung cancer cell lines were initially irradiated to generate ionizing radiation (IR)-resistant lung cancer cell lines. RNA-seq analysis was used to examine the whole-transcriptome alteration in IR-resistant lung cancer cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of LC-C and the target gene ErbB receptor feedback inhibitor 1 (ERRFI1) on radiosensitivity of IR-resistant lung cancer cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blotting was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of IR-resistant lung cancer cells in vivo.ResultsCompared with parental cells, IR-resistant lung cancer cells were more resistant to radiation. LC-C significantly enhanced the effect of radiation in IR-resistant lung cancer cells both in vitro and in vivo and validated ERRFI1 as a candidate downstream gene by RNA-seq. Forced expression of ERRFI1 alone could significantly increase the radiosensitivity of IR-resistant lung cancer cells, while silencing of ERRFI1 attenuated the radiosensitizing function of LC-C. Accordingly, LC-C and ERRFI1 effectively inhibited IR-induced DNA damage repair, and ERRFI1 significantly induced G2/M checkpoint arrest. Additional investigations revealed that down-regulation of EGFR/STAT3 pathway played an important role in radiosensitization between ERRFI1 and LC-C. Furthermore, the high expression level of ERRFI1 was associated with high overall survival rates in lung cancer patients.ConclusionsTreatment of LC-C may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a potential therapeutic target in NSCLC.
Highlights
Lung cancer is the leading cause of cancer related death worldwide [1, 2], and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases
Colony formation assay showed that A549-IR cells were more resistant to radiation than A549 cells, and LC-C significantly radiosensitized A549-IR cells as the surviving fractions at 2 Gy (SF2) was reduced in the LC-C group compared to the control group (0.27 ± 0.03 vs. 0.91 ± 0.05, P < 0.01) (Figures 1B–D), indicating a potential radiosensitization effect of LC-C on ionizing radiation-resistant A549-IR cells
Colony formation assay showed that 2.5 mM LC-C significantly radiosensitized H1299-IR cells as the SF2 was reduced in the LC-C group compared to the control group (0.53 ± 0.04 vs. 0.77 ± 0.02, P < 0.05) (Figures 2B–D)
Summary
Lung cancer is the leading cause of cancer related death worldwide [1, 2], and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases. Despite major advances in the field of radiotherapy technology during the past decades [3, 4], the prognosis for 5-year survival rate in patients with inoperable locally advanced NSCLC is still poor (approximately 12–24%) [5] due to radioresistance related local recurrence [6]. Increasing radiation dose is an important strategy for overcoming radiation tolerance; the risk of normal tissue toxicity always limits the dose escalation [7, 8]. The mechanism of radioresistance has not been well clarified yet, and effective radiosensitization strategies are urgently needed in the clinic. It is crucial to find new therapeutic targets and/or drugs to overcome radioresistance without increasing the adverse effects, and natural products have been considered as promising candidates of radiosensitizers [13, 14]
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