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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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Reciprocal activation of NOX/Akt and IL-6/JAK1/STAT3 signalings in vivo(A) The effect of IL-6 on NOX4 expression in vivo analyzed by immunohistochemistry. (B) The effect of IL-6 on pAkt expression level, and the ratio of pAkt to total Akt was determined by ELISA assay. (C) The effects of NOX4 overexpression of NOX4 knockdown on IL-6 production in A549 tumor tissues assayed by ELISA. (D-E) The effects of NOX4 overexpression of NOX4 knockdown on p-STAT3 or p-JAK1 expression levels in A549 tumor tissues analyzed by immunohistochemistry. All scale bars represent 50 μm. *P < 0.05.
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Figure 9: Reciprocal activation of NOX/Akt and IL-6/JAK1/STAT3 signalings in vivo(A) The effect of IL-6 on NOX4 expression in vivo analyzed by immunohistochemistry. (B) The effect of IL-6 on pAkt expression level, and the ratio of pAkt to total Akt was determined by ELISA assay. (C) The effects of NOX4 overexpression of NOX4 knockdown on IL-6 production in A549 tumor tissues assayed by ELISA. (D-E) The effects of NOX4 overexpression of NOX4 knockdown on p-STAT3 or p-JAK1 expression levels in A549 tumor tissues analyzed by immunohistochemistry. All scale bars represent 50 μm. *P < 0.05.

Mentions: To explore the mechanism underlying the functional interplay of NOX4 and IL-6 in enhancing A549 tumor growth and survival of NSCLC cells in vivo, we sought to determine the reciprocal activation between NOX4/Akt and IL-6/STAT3 signalings in vivo. Fig. 9A showed that IL-6 treatment caused much more levels of NOX4 expression in vivo as determined by immunohistochemistry assay, as well as significantly enhanced levels of pAkt as determined by ELISA (Fig. 9B). On the other hand, the results obtained from ELISA assay showed that NOX4-transduced A549 cells produced more levels of IL-6 compared with control (Fig. 9C). Immunohistochemistry analysis showed that NOX4-transduced A549 tumors displayed higher activity of JAK1 and STAT3 (Fig. 9D and E). In contrast, NOX4 depletion resulted in lower levels of IL-6 and lower activity of JAK1 and STAT3 compared with control in vivo (Fig. 9C, D and E).


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)

Reciprocal activation of NOX/Akt and IL-6/JAK1/STAT3 signalings in vivo(A) The effect of IL-6 on NOX4 expression in vivo analyzed by immunohistochemistry. (B) The effect of IL-6 on pAkt expression level, and the ratio of pAkt to total Akt was determined by ELISA assay. (C) The effects of NOX4 overexpression of NOX4 knockdown on IL-6 production in A549 tumor tissues assayed by ELISA. (D-E) The effects of NOX4 overexpression of NOX4 knockdown on p-STAT3 or p-JAK1 expression levels in A549 tumor tissues analyzed by immunohistochemistry. All scale bars represent 50 μm. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Reciprocal activation of NOX/Akt and IL-6/JAK1/STAT3 signalings in vivo(A) The effect of IL-6 on NOX4 expression in vivo analyzed by immunohistochemistry. (B) The effect of IL-6 on pAkt expression level, and the ratio of pAkt to total Akt was determined by ELISA assay. (C) The effects of NOX4 overexpression of NOX4 knockdown on IL-6 production in A549 tumor tissues assayed by ELISA. (D-E) The effects of NOX4 overexpression of NOX4 knockdown on p-STAT3 or p-JAK1 expression levels in A549 tumor tissues analyzed by immunohistochemistry. All scale bars represent 50 μm. *P < 0.05.
Mentions: To explore the mechanism underlying the functional interplay of NOX4 and IL-6 in enhancing A549 tumor growth and survival of NSCLC cells in vivo, we sought to determine the reciprocal activation between NOX4/Akt and IL-6/STAT3 signalings in vivo. Fig. 9A showed that IL-6 treatment caused much more levels of NOX4 expression in vivo as determined by immunohistochemistry assay, as well as significantly enhanced levels of pAkt as determined by ELISA (Fig. 9B). On the other hand, the results obtained from ELISA assay showed that NOX4-transduced A549 cells produced more levels of IL-6 compared with control (Fig. 9C). Immunohistochemistry analysis showed that NOX4-transduced A549 tumors displayed higher activity of JAK1 and STAT3 (Fig. 9D and E). In contrast, NOX4 depletion resulted in lower levels of IL-6 and lower activity of JAK1 and STAT3 compared with control in vivo (Fig. 9C, D and E).

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