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STAT1 modification improves therapeutic effects of interferons on lung cancer cells.

Chen J, Zhao J, Chen L, Dong N, Ying Z, Cai Z, Ji D, Zhang Y, Dong L, Li Y, Jiang L, Holtzman MJ, Chen C - J Transl Med (2015)

Bottom Line: We found that expression of STAT1 or STAT1-CC enhanced the effect of IFN-γ and, IFN-β on inhibition of human lung cancer cell proliferation, migration and invasiveness.STAT1-CC showed increased effects compared to STAT1 on IFN-γ induced pSTAT1 and down-regulation of S100A4, PCNA, and c-fos levels.The results show that STAT1-CC exhibited more strength in improving the antitumor response of IFNs in lung cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. jiestory414@163.com.

ABSTRACT

Background: Interferons (IFNs) have potent anti-proliferative, pro-apoptotic, and immunomodulatory activities against cancer. However, the clinical utility of IFNs is limited by toxicity and pharmacokinetics making it difficult to achieve sustained therapeutic levels especially in solid tumors.

Methods: Signal Transducer and Activator of Transcription 1 (STAT1) or a modified STAT1 (designated STAT1-CC) that is hyper-responsive to IFN were overexpressed in lung cancer SPC-A-1 and H1299 cells using lentiviral vectors. Transduction efficiency was monitored using enhanced green fluorescent protein (EGFP) expression. After transduction, cells were treated with interferon-gamma (IFN-γ) or interferon-beta (IFN-β) and monitored for cell proliferation, migration, and invasiveness using Cell Counting Kit-8 and transwell chamber assays and for apoptosis using Annexin V detection by flow cytometry. In addition, levels of STAT1, STAT1 Tyr-701 phosphorylation (pSTAT1), fibronectin, and β-catenin were determined using western blotting. In the case of IFN-γ stimulation, levels of S100A4, proliferating cell nuclear antigen (PCNA), and c-fos expression were also determined.

Results: We found that expression of STAT1 or STAT1-CC enhanced the effect of IFN-γ and, IFN-β on inhibition of human lung cancer cell proliferation, migration and invasiveness. Moreover, STAT1 and STAT1-CC expression caused increases in pSTAT1 and decreases in fibronectin and β-catenin levels. STAT1-CC showed increased effects compared to STAT1 on IFN-γ induced pSTAT1 and down-regulation of S100A4, PCNA, and c-fos levels.

Conclusion: The results show that STAT1-CC exhibited more strength in improving the antitumor response of IFNs in lung cancer cells. Results from this study suggest that combined treatment of IFNs and STAT1-CC might be a feasible approach for the clinical management of lung cancer in the future.

No MeSH data available.


Related in: MedlinePlus

Overexpression of STAT1-CC improves IFN-induced growth inhibition in lung cancer cells. a, b SPC-A-1 cell growth inhibition rate was determined in each group treated with various doses of IFN-γ or IFN-β for 6 days (*P < 0.05, **P < 0.01). c, d H1299 cell growth was assayed in each group treated with IFN-γ 1000 U/ml or IFN-β 1000 U/ml for 2 days. e, f SPC-A-1 cell growth curve was plotted at various time points for each group treated with IFN-γ 1000 or 10,000 U/ml. g, h SPC-A-1 cell growth curves were plotted at various time points for each group treated with IFN-β 1000 or 10,000 U/ml
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Fig4: Overexpression of STAT1-CC improves IFN-induced growth inhibition in lung cancer cells. a, b SPC-A-1 cell growth inhibition rate was determined in each group treated with various doses of IFN-γ or IFN-β for 6 days (*P < 0.05, **P < 0.01). c, d H1299 cell growth was assayed in each group treated with IFN-γ 1000 U/ml or IFN-β 1000 U/ml for 2 days. e, f SPC-A-1 cell growth curve was plotted at various time points for each group treated with IFN-γ 1000 or 10,000 U/ml. g, h SPC-A-1 cell growth curves were plotted at various time points for each group treated with IFN-β 1000 or 10,000 U/ml

Mentions: Under basal culture conditions, both STAT1 and STAT1-CC have similar effects on inhibition of lung cancer cell growth (Fig. 2b), but since in the previous studies, STAT1-CC demonstrated hyper-responsive to IFN stimulation [11], we stimulated the cells with various concentrations of IFNs. Although STAT1 effectively enhanced IFN-γ (1000 U/ml) or IFN-β (1000 U/ml) induced inhibition of growth at 39.7 and 24.1 %, respectively in SPC-A-1 cells, transduction with STAT1-CC resulted in a greater effect on inhibition of cell growth at 54.9 and 39.9 %, when cells were treated with the same concentrations of IFN-γ or IFN-β (Fig. 4a, b, e–h). A similar profile was observed in H1299-expressing STAT1 cells at inhibition rates of 40.2 and 53.5 % for IFN-γ and IFN-β, while inhibition rates of 75.4 and 77.0 % were achieved in STAT1-CC cells (Fig. 4c, d). These data indicated that STAT1-CC exhibits stronger inhibition of lung cancer cell growth with IFN treatment.Fig. 4


STAT1 modification improves therapeutic effects of interferons on lung cancer cells.

Chen J, Zhao J, Chen L, Dong N, Ying Z, Cai Z, Ji D, Zhang Y, Dong L, Li Y, Jiang L, Holtzman MJ, Chen C - J Transl Med (2015)

Overexpression of STAT1-CC improves IFN-induced growth inhibition in lung cancer cells. a, b SPC-A-1 cell growth inhibition rate was determined in each group treated with various doses of IFN-γ or IFN-β for 6 days (*P < 0.05, **P < 0.01). c, d H1299 cell growth was assayed in each group treated with IFN-γ 1000 U/ml or IFN-β 1000 U/ml for 2 days. e, f SPC-A-1 cell growth curve was plotted at various time points for each group treated with IFN-γ 1000 or 10,000 U/ml. g, h SPC-A-1 cell growth curves were plotted at various time points for each group treated with IFN-β 1000 or 10,000 U/ml
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4562290&req=5

Fig4: Overexpression of STAT1-CC improves IFN-induced growth inhibition in lung cancer cells. a, b SPC-A-1 cell growth inhibition rate was determined in each group treated with various doses of IFN-γ or IFN-β for 6 days (*P < 0.05, **P < 0.01). c, d H1299 cell growth was assayed in each group treated with IFN-γ 1000 U/ml or IFN-β 1000 U/ml for 2 days. e, f SPC-A-1 cell growth curve was plotted at various time points for each group treated with IFN-γ 1000 or 10,000 U/ml. g, h SPC-A-1 cell growth curves were plotted at various time points for each group treated with IFN-β 1000 or 10,000 U/ml
Mentions: Under basal culture conditions, both STAT1 and STAT1-CC have similar effects on inhibition of lung cancer cell growth (Fig. 2b), but since in the previous studies, STAT1-CC demonstrated hyper-responsive to IFN stimulation [11], we stimulated the cells with various concentrations of IFNs. Although STAT1 effectively enhanced IFN-γ (1000 U/ml) or IFN-β (1000 U/ml) induced inhibition of growth at 39.7 and 24.1 %, respectively in SPC-A-1 cells, transduction with STAT1-CC resulted in a greater effect on inhibition of cell growth at 54.9 and 39.9 %, when cells were treated with the same concentrations of IFN-γ or IFN-β (Fig. 4a, b, e–h). A similar profile was observed in H1299-expressing STAT1 cells at inhibition rates of 40.2 and 53.5 % for IFN-γ and IFN-β, while inhibition rates of 75.4 and 77.0 % were achieved in STAT1-CC cells (Fig. 4c, d). These data indicated that STAT1-CC exhibits stronger inhibition of lung cancer cell growth with IFN treatment.Fig. 4

Bottom Line: We found that expression of STAT1 or STAT1-CC enhanced the effect of IFN-γ and, IFN-β on inhibition of human lung cancer cell proliferation, migration and invasiveness.STAT1-CC showed increased effects compared to STAT1 on IFN-γ induced pSTAT1 and down-regulation of S100A4, PCNA, and c-fos levels.The results show that STAT1-CC exhibited more strength in improving the antitumor response of IFNs in lung cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. jiestory414@163.com.

ABSTRACT

Background: Interferons (IFNs) have potent anti-proliferative, pro-apoptotic, and immunomodulatory activities against cancer. However, the clinical utility of IFNs is limited by toxicity and pharmacokinetics making it difficult to achieve sustained therapeutic levels especially in solid tumors.

Methods: Signal Transducer and Activator of Transcription 1 (STAT1) or a modified STAT1 (designated STAT1-CC) that is hyper-responsive to IFN were overexpressed in lung cancer SPC-A-1 and H1299 cells using lentiviral vectors. Transduction efficiency was monitored using enhanced green fluorescent protein (EGFP) expression. After transduction, cells were treated with interferon-gamma (IFN-γ) or interferon-beta (IFN-β) and monitored for cell proliferation, migration, and invasiveness using Cell Counting Kit-8 and transwell chamber assays and for apoptosis using Annexin V detection by flow cytometry. In addition, levels of STAT1, STAT1 Tyr-701 phosphorylation (pSTAT1), fibronectin, and β-catenin were determined using western blotting. In the case of IFN-γ stimulation, levels of S100A4, proliferating cell nuclear antigen (PCNA), and c-fos expression were also determined.

Results: We found that expression of STAT1 or STAT1-CC enhanced the effect of IFN-γ and, IFN-β on inhibition of human lung cancer cell proliferation, migration and invasiveness. Moreover, STAT1 and STAT1-CC expression caused increases in pSTAT1 and decreases in fibronectin and β-catenin levels. STAT1-CC showed increased effects compared to STAT1 on IFN-γ induced pSTAT1 and down-regulation of S100A4, PCNA, and c-fos levels.

Conclusion: The results show that STAT1-CC exhibited more strength in improving the antitumor response of IFNs in lung cancer cells. Results from this study suggest that combined treatment of IFNs and STAT1-CC might be a feasible approach for the clinical management of lung cancer in the future.

No MeSH data available.


Related in: MedlinePlus