Abstract
Artocarpin has been shown to exhibit cytotoxic effects on different cancer cells, including non-small cell lung carcinoma (NSCLC, A549). However, the underlying mechanisms remain unclear. Here, we explore both p53-dependent and independent apoptosis pathways in artocarpin-treated NSCLC cells. Our results showed that artocarpin rapidly induced activation of cellular protein kinases including Erk1/2, p38 and AktS473. Inhibition of these protein kinases prevented artocarpin-induced cell death. Moreover, artocarpin-induced phosphorylation of these protein kinases and apoptosis were mediated by induction of reactive oxygen species (ROS), as pretreatment with NAC (a ROS scavenger) and Apocynin (a Nox-2 inhibitor) blocked these events. Similarly, transient transfection of p47Phox or p91Phox siRNA attenuated artocarpin-induced NADPH oxidase activity and cell death. In addition, p53 dependent apoptotic proteins including PUMA, cytochrome c, Apaf-1 and caspase 3 were activated by artocarpin, and these effects can be abolished by antioxidants, MAPK inhibitors (U0126 and SB202190), but not by PI3K inhibitor (LY294002). Furthermore, we found that artocarpin-induced Akt phosphorylation led to increased NF-κB activity, which may act as an upstream regulator in the c-Myc and Noxa pathway. Therefore, we propose that enhancement of both ERK/ p38/ p53-dependent or independent AktS473/NF-κB/c-Myc/Noxa cascade by Nox-derived ROS generation plays an important role in artocarpin-induced apoptosis in NSCLC cells.
Highlights
Lung cancer, which causes about 1.59 million deaths a year, is a very common cancer and a major cause of death worldwide [1]
We first determined the anti-proliferative activities of artocarpin (Figure 1A) in the human nonsmall cell lung cancer (NSCLC) cell lines A549, H226 and H1299 using the sulforhodamine B (SRB) assay
We clearly demonstrate that artocarpin dose-dependently suppressed the proliferation of nonsmall cell lung cancer (NSCLC) cell lines, but showed much less activity in normal human pulmonary epithelial cells (HPAEpiCs)
Summary
Lung cancer, which causes about 1.59 million deaths a year, is a very common cancer and a major cause of death worldwide [1]. Insufficient apoptosis may result in uncontrolled cell proliferation and has been shown to be involved in various diseases, such as cancer [2,3,4]. Chemotherapy and γ-irradiation are major therapeutic modalities to decrease cancer cell proliferation in clinical medicine, but these therapies may kill normal cells and lead to many side effects in human body, such as loss of immunity. Erridge et al revealed that the five-year survival rate in lung cancer cases is less than 15% due to patient resistance to γ-radiation, chemotherapy and surgical intervention [5, 6]. Many researchers and pharmaceutical industries have been enthusiastically developing novel anticancer agents to increase the survival rate and improve life quality of lung cancer patients [7,8,9]
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