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Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells.

Li J, Lan T, Zhang C, Zeng C, Hou J, Yang Z, Zhang M, Liu J, Liu B - Oncotarget (2015)

Bottom Line: Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer.Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC).The in vivo results were similar to those obtained in vitro.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China.

ABSTRACT
Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling.

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NOX4 interplays with IL-6 to regulate A549 cell proliferation and survival in vitro(A) The effects of IL-6, P6, or siltuximab on the proliferation of NOX4-transfected A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 group, P < 0.05. (B) The effect of IL-6 on the proliferation of NOX4-depleted A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 shRNA group, P < 0.05. (C) The effect of IL-6 on cell apoptosis of NOX4-depleted A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 shRNA group, P < 0.05.
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Figure 5: NOX4 interplays with IL-6 to regulate A549 cell proliferation and survival in vitro(A) The effects of IL-6, P6, or siltuximab on the proliferation of NOX4-transfected A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 group, P < 0.05. (B) The effect of IL-6 on the proliferation of NOX4-depleted A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 shRNA group, P < 0.05. (C) The effect of IL-6 on cell apoptosis of NOX4-depleted A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 shRNA group, P < 0.05.

Mentions: We further evaluated the biological significance of the reciprocal regulation between NOX4 and IL-6/STAT3 pathway in the growth and survival of A549 cells. As shown in Fig. 5A, NOX4 overexpression substantially promoted A549 cell growth. Additional IL-6 treatment in NOX4-transfected A549 cells led to a further increase in cell growth, whereas either P6 (2.5 μM) or siltuximab (20 μg/mL) could partially reverse NOX4-mediated growth-promoting effect in these cells. Furthermore, NOX4 depletion substantially suppressed cell growth, but additional IL-6 administration greatly rescued growth of NOX4-depleted cells (Fig. 5B). The data from flow cytometry assay also indicated that IL-6 administration could, at least partially, reverse the enhancement effect of NOX4 depletion on A549 cell apoptosis (Fig. 5C). Collectively, these results indicate that NOX4 and IL-6/STAT3 pathway are functionally interdependent in promoting A549 cell proliferation and survival.


Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells.

Li J, Lan T, Zhang C, Zeng C, Hou J, Yang Z, Zhang M, Liu J, Liu B - Oncotarget (2015)

NOX4 interplays with IL-6 to regulate A549 cell proliferation and survival in vitro(A) The effects of IL-6, P6, or siltuximab on the proliferation of NOX4-transfected A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 group, P < 0.05. (B) The effect of IL-6 on the proliferation of NOX4-depleted A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 shRNA group, P < 0.05. (C) The effect of IL-6 on cell apoptosis of NOX4-depleted A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 shRNA group, P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359215&req=5

Figure 5: NOX4 interplays with IL-6 to regulate A549 cell proliferation and survival in vitro(A) The effects of IL-6, P6, or siltuximab on the proliferation of NOX4-transfected A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 group, P < 0.05. (B) The effect of IL-6 on the proliferation of NOX4-depleted A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 shRNA group, P < 0.05. (C) The effect of IL-6 on cell apoptosis of NOX4-depleted A549 cells. Bars are mean ± SD from four independent experiments. *Significantly different from control, P < 0.05. #Significantly different from NOX4 shRNA group, P < 0.05.
Mentions: We further evaluated the biological significance of the reciprocal regulation between NOX4 and IL-6/STAT3 pathway in the growth and survival of A549 cells. As shown in Fig. 5A, NOX4 overexpression substantially promoted A549 cell growth. Additional IL-6 treatment in NOX4-transfected A549 cells led to a further increase in cell growth, whereas either P6 (2.5 μM) or siltuximab (20 μg/mL) could partially reverse NOX4-mediated growth-promoting effect in these cells. Furthermore, NOX4 depletion substantially suppressed cell growth, but additional IL-6 administration greatly rescued growth of NOX4-depleted cells (Fig. 5B). The data from flow cytometry assay also indicated that IL-6 administration could, at least partially, reverse the enhancement effect of NOX4 depletion on A549 cell apoptosis (Fig. 5C). Collectively, these results indicate that NOX4 and IL-6/STAT3 pathway are functionally interdependent in promoting A549 cell proliferation and survival.

Bottom Line: Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer.Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC).The in vivo results were similar to those obtained in vitro.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China.

ABSTRACT
Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling.

Show MeSH
Related in: MedlinePlus