Curcumin inhibits the invasion of lung cancer cells by modulating the PKCα/Nox-2/ROS/ATF-2/MMP-9 signaling pathway

Abstract

Invasion and metastasis are the major causes of tumor-related mortality in lung cancer. It is believed that curcumin is an effective drug possessing anti-invasive and anti-metastatic activities in the treatment of cancer. However, the specific mechanisms remain unclear. In the present study, we investigated whether the PKCα/Nox-2/ATF-2/MMP-9 signaling pathway is involved in the invasive behavior of lung cancer and whether curcumin could inhibit invasion by modulating this pathway. The cytotoxic effect of curcumin was evaluated by MTT assay and the capacity of invasion was assessed by Transwell assay. siRNA and plasmid transfection techniques were used to study the function of targeted genes. Real-time PCR and western blot analysis were used to evaluate the expression levels of PKCα, Nox-2, MMP-9 and the phosphorylation of ATF-2. The results showed that curcumin inhibited the proliferation and invasion of A549 cells in a dose-dependent manner. Overexpression of MMP-9 enhanced the invasion of A549 cells. However, inhibition of MMP-9 by siRNA or curcumin suppressed cell invasion. Moreover, we also demonstrated the catalytic role of PKCα in expression of MMP-9 and cellular invasion in A549 cells, which was dependent on the expression of Nox-2 and phosphorylation of ATF-2. Finally, we also showed that curcumin dose-dependently reduced the expression of PKCα, P47phox, Nox-2 and phosphorylated ATF-2, as well as intracellular ROS generation, suggesting the inhibitory effect of curcumin on the activation of the PKCα/Nox-2/ROS/ATF-2 pathway. In conclusion, the PKCα/Nox-2/ROS/ATF-2/MMP-9 signaling pathway is activated in lung cancer A549 cells, which could be modulated by curcumin to inhibit cell invasiveness.

Mechanistic Understanding of Curcumin’s Therapeutic Effects in Lung Cancer

“…Activated ATF2 then facilitates AP1-binding to the MMP-9 promoter resulting in MMP-9 expression. This study demonstrated that inhibition of PKCα/NOX-2/ROS/ATF2 signaling pathway decreases expression of MMP-9, suggesting one of the mechanisms of anti-invasive effect by curcumin in lung cancer cells [192].…”

NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells

“…As recent research has brought some light into the mechanisms of NOX-derived ROS action and effects on proliferation, invasiveness, metastasis, and angiogenesis of cancer cells, NOX have been proposed as targets in therapy of lung, colon, thyroid, and prostate cancer [51, 147, 148]. Especially, the ability to prevent metastasis through the modulation of cancer stem cell growth and proliferation would bring enormous benefits for patients.…”

Expression of Matrix Metalloproteinase‐9 and CD34 in Giant Cell Tumor of Bone

“…Ueda et al have reported that MMP-9 is clearly up-regulated in GCTB cells, implying that MMP-9 plays an important role in dissolution of collagen-based bone matrix 26 . Expression and localization of MMP-9 have been detected by immunohistochemistry and hybridization in situ within GCTB and published data have shown that MMP-9 is associated with local recurrence of tumor [27][28][29][30] . However, these studies did not identify a relationship between MVD and MMP-9 expression; neither did they identify a relationship between MMP-9 expression and the risk of recurrence and prognosis of GCTB.…”