A Mulberry Diels-Alder-Type Adduct, Kuwanon M, Triggers Apoptosis and Paraptosis of Lung Cancer Cells through Inducing Endoplasmic Reticulum Stress

The mulberry tree (Morus alba) has been cultivated in China for thousands of years. Mulberry Diels-Alder-type adducts (MDAAs) are characteristic constituents of the genus Morus. The unique structure and diverse bioactivities of MDAAs have attracted the attention of researchers. Kuwanon M (KWM) is an MDAA isolated from the root bark of Morus alba. This research reports the growth inhibitory effects of KWM on human lung cancer cells and its possible mechanism. In A549 and NCI-H292 cells, KWM treatment induced suppression of cell proliferation and migration. The appearance of chromatin condensation, phosphatidyl serine exposure and caspase cleavage indicated the arising of apoptosis. The loss of mitochondrial membrane potential (MMP), release of cytochrome c and dysregulation of Bax/Bcl-2 demonstrated that the KWM-induced apoptosis was through the mitochondrial pathway. Paraptosis was simultaneously detected under KWM treatment, as evidenced by the exhibition of cytoplasmic vacuolation, down-regulation of Alix and up-regulation of endoplasmic reticulum (ER) stress-related proteins. Mechanistically, ER stress induced activation of unfolded protein response (UPR) pathways and activation of the MAPK (JNK and ERK) pathway, all of which were critical for KWM-induced apoptosis and paraptosis. These findings suggested the possibility that KWM might be considered as a potential lung cancer therapeutic agent.