In this study, we investigated the relationship between Cal and apoptosis in A549 cells and found that Cal induced apoptosis in these cells. We then attempted to elucidate the mechanism underlying the induction of A549 cell apoptosis by Cal.
The MAPK signaling pathway plays an important role in major cellular processes including proliferation and apoptosis. MAPKs consist of kinases such as p38MAPK and ERK1/2 [11, 12], and the former is involved in inducing apoptosis [13]. Kong et al. reported that the activation of p38MAPK and suppression of ERK1/2 plays a central role in the apoptosis of diffuse large B cell lymphoma cells [14]. Furthermore, Ye et al. showed the induction of apoptosis by p38MAPK activation in A549 NSCLC cells [15]. In this study, we examined the relationship between Cal and MAPKs and showed that the levels of cytoplasmic p38MAPK, but not ERK1/2, in A549 cells were activated in the presence of Cal.
Idiopathic pulmonary fibrosis (IPF) occasionally occurs in patients with lung cancer (largely NSCLC) because of smoking history or complication such as emphysema [16–18]; however, the mechanism by which it occurs remains mostly unknown. Chemotherapy or radiation therapy are effective for NSCLC, however these therapies occasionally induce pulmonary fibrosis and so these are not selectable for NSCLC complicated with pulmonary fibrosis.
We previously reported that Cal prevented bleomycin-induced pulmonary fibrosis in mice [19]. Cal also decreases the expression of IL-6, TGF-β1, angiopoietin-1, and collagen type Iα1 mRNA in mouse lung tissues. In vitro studies showed that Cal decreased the production of IL-6, TGF-β1, and angiopoietin-1 as well as the synthesis of collagen by lung fibroblasts. Furthermore, Cal decreased IL-6-dependent proliferation and angiopoietin-1-dependent migration of lung fibroblasts. These may be possible mechanisms by which Cal suppresses pulmonary fibrosis.
We previously reported that Cal prevents A549 NSCLC cell proliferation [8]. Moreover, we showed that Cal induced apoptosis in A549 cells in this study, suggesting its clinical application in patients with NSCLC complicated with IPF.
In summary, we demonstrated the apoptosis-inducing effects of Cal in A549 cells which may have been due to the activation of p38MAPK. Although the precise cellular mechanism underlying the Cal-induced apoptosis of A549 cell is not fully understood, our results may lead to the development of novel strategies for the treatment of NSCLC.