Figure 6

Schematic diagram of the proposed molecular mechanisms of fisetin-induced G2/M arrest, apoptosis, and autophagy in uterine leiomyomas. The schematic diagram delineates the extrinsic (death receptor) and intrinsic (mitochondrial) pathways of fisetin-induced apoptosis. Fisetin may induce apoptosis through both pathways. Mitochondria act as major control points involving the regulation of apoptosis. Uterine leiomyomas cells were exposed to fisetin, and the phagosomes were converted to double-layered membranes of autophagosomes through increasing expression levels of Atg proteins including Beclin-1and Atg-7, while LC3-I is converted to LC3-II. The inhibition of the Akt/mTOR signaling pathway contributes to the accumulation of LC3-II, which suggests that the pathway is upstream of fisetin-induced autophagy. Once the autophagosome develops, its maturation is complete upon fusion with a lysosome to form an autophagolysosome. Eventually, fisetin induces programmed cell death. In addition, phosphorylation of p53 stimulates its activation of p21, resulting in cell cycle arrest in G2/M through inhibiting cyclin B1 (CCNB1) expression and activity.