Luteolin Inhibits Proliferation and Induces Apoptosis of Human Placental Choriocarcinoma Cells by Blocking the PI3K/AKT Pathway and Regulating Sterol Regulatory Element Binding Protein Activity

Abstract

Luteolin is a natural compound known for its anticancer effects on various human cancers by regulating signal transduction cascades. However, the effects of luteolin on human placental choriocarcinoma are not known. Results of the present study revealed that luteolin decreased viability of JAR and JEG-3 cells, which are valuable placental models, in a dose-dependent manner, and it induced apoptosis and loss of mitochondrial membrane potential in JAR and JEG-3 cells. The results also suggested that the PI3K/AKT pathway was inhibited by luteolin treatment of JAR and JEG-3 cells in a dose- and time-dependent manner. Next, we established effects of luteolin in the presence of pharmacological inhibitors of PI3K/AKT, ERK1/2 MAPK, and mTOR on proliferation of JAR and JEG-3 cells. In addition, these inhibitors were used to verify phosphorylation of AKT, GSK3beta, and ERK1/2 and to confirm mechanisms regulated by luteolin in JAR and JEG-3 cells. We also determined levels of SREBP1 and SREBP2 expression to investigate regulatory functions of luteolin in lipid metabolism in JAR and JEG-3 cells. Expression levels of both SREBP1 and SREBP2 mRNAs were significantly reduced, but only SREBP1 protein was influenced by luteolin. We compared viability of JAR and JEG-3 cells in response to luteolin alone or in combination with other chemotherapeutic drugs (etoposide, cisplatin, and paclitaxel) and found that luteolin has synergistic effects with the conventional chemotherapeutic drugs as an anticancer agent. Collectively, these results showed that luteolin plays an important role in the treatment of human choriocarcinoma cells by inhibiting the PI3K/AKT/mTOR/SREBP cascade and expression of lipogenic genes.

The Akt pathway in oncology therapy and beyond (Review)

“…Jaceosidin is a flavone from Artemisia princeps , a traditional medicinal herb, with a marked effect on oral squamous cell carcinoma by Akt downregulation ( 133 ). The antiproliferative and antiinflammatory effect of luteolin via the inactivation of PI3K/Akt pathway has also been demonstrated by several studies ( 134 , 135 ).…”

Down‐regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP‐1c axis

“…It is known that mTOR plays an essential role in de novo lipid synthesis including fatty acid and cholesterol synthesis (Hao et al, 2013). One of the downstream molecules of the PI3K/AKT/mTOR pathway is SREBP, which acts as an intracellular sterol sensor (Lim, Yang, Bazer & Song, 2016). Furthermore, SREBP-1c is required for cell survival and tumorigenesis in glioblastoma and breast cancers, and it has been reported that the Akt/mTOR pathway stimulates SREBP-1cdependent lipogenesis (Guo, Bell, Mischel, & Chakravarti, 2014).…”

Matrine inhibits the invasive and migratory properties of human hepatocellular carcinoma by regulating epithelial‑mesenchymal transition

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