Artocarpin, an isoprenyl flavonoid, induces p53-dependent or independent apoptosis via ROS-mediated MAPKs and Akt activation in non-small cell lung cancer cells

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.

Role of NOX2-Derived Reactive Oxygen Species in NK Cell–Mediated Control of Murine Melanoma Metastasis

“…High endogenous ROS concentrations in malignant cells may also render these cells more vulnerable to further stresses (34,39,40). Hence, anticancer therapies that trigger a further increase in ROS formation may induce cell death in cancer cells compared with their non-malignant counterparts (34,41,42). In addition, ROS can limit malignant growth by triggering activation of p53, whereas antioxidants enhanced tumor progression in a p53-dependent manner (17).…”

Upregulation and activation of p53 by erastin‑induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells

“…Erastin-induced ferroptotic cell death is dependent on the increased level of intracellular reactive oxygen species (ROS), which are widely believed to act as a mediator of apoptosis. Tsai et al (8) found that, in A549 non-small cell lung cancer cells, the activation of p53-dependent apoptotic proteins, including PUMA, cytochrome c, Apaf-1 and caspase-3, was dependent on the presence of ROS. Accumulated ROS were also reported to regulate the expression and activation of p53, and the ROS/p53 pathway was found to regulate several cellular physiological processes, including cell senescence (9), oxidative protection (10) and apoptosis (11).…”

Molecular mechanisms of natural compounds in cell death induction and sensitization to chemotherapeutic drugs in lung cancer

“…Artocarpin, another flavonoid, is isolated from Artocarpus species such as Artocarpus heterophyllus , which is found in Southeast Asia and has long been used in agriculture, food, and traditional medicine. Artocarpin exerts anticancer activity by mediating apoptosis via ROS induction and suppression of the p38 MAPK, ERK1/2, and Akt signaling pathways in lung cancer cells (Tsai et al, ). Several studies have suggested that the MAPK and PI3K/Akt (phosphoinositide 3‐kinase/protein kinase B) pathways are targets for flavonoid‐mediated apoptosis.…”

“…Oxidative stress caused by this compound diminished ERK1/2 and p38 MAPK signaling, contributing to p53 activation and subsequently promoting PUMA expression and stimulating caspase‐3 cleavage. The latter mechanism was involved with inhibition of Akt phosphorylation, which in turn mediates NF‐κB, an upstream regulator of the c‐Myc and Noxa pathways (Tsai et al, ).…”