Luteolin Promotes Cell Apoptosis by Inducing Autophagy in Hepatocellular Carcinoma

Abstract

Background/Aims: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. Luteolin, a flavonoid from traditional Chinese medicine, shows anti-cancer activity in many cancer cells, including HCC. However, the mechanism underlying the action of luteolin in HCC, especially its role in regulating cell autophagy, remains unclear. In the present study, we investigated the role of luteolin in regulating cell autophagy and the role of autophagy in luteolin-induced apoptosis. Methods: The 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay (MTT) was used to investigate cell viability. Flow cytometry analysis was used to detect the cell cycle and cell apoptosis. Hoechst 33342 staining was used to detect cell apoptosis. Transmission electron microscopy was used to investigate autophagy. qRT-PCR and western blotting were used to detect apoptosis- and autophagy-related mRNAs and proteins. Results: Luteolin reduced the viability of SMMC-7721 cells in a time and dose-dependent manner, and induced significant G0/G1-phase arrest. In addition, the results of flow cytometry analysis and Hoechst 33342 staining showed that luteolin treatment increased the number of apoptotic cells obviously, and the results of qRT-PCR and western blotting showed that luteolin treatment increased caspase 8 and decreased bcl-2 at the mRNA and protein levels. Furthermore, luteolin increased the number of intracellular autophagosomes, promoted LC3B-I conversion to LC3B-II, and increased Beclin 1 expression. Finally, co-treatment with the autophagy inhibitor chloroquine weakened the effects of luteolin on cell apoptosis. Conclusion: Luteolin induced apoptosis in human liver cancer SMMC-7721 cells, partially via autophagy. Thus, luteolin could be used as a regulator of autophagy in HCC treatment.

Luteolin Exerts Neuroprotection via Modulation of the p62/Keap1/Nrf2 Pathway in Intracerebral Hemorrhage

“…Our present findings were similar to those described above. In addition, luteolin has been found to enhance autophagy in studies of other diseases (Xu et al, 2014;Hu et al, 2016;Cao et al, 2017). Additionally, the administration of autophagic inhibitors such as CQ, has been shown to be associated with exacerbating disease progression (Yang et al, 2018a;Wu et al, 2019).…”

<p>Delivery luteolin with folacin-modified nanoparticle for glioma therapy</p>

“…Luteolin has a broad-spectrum antitumor effect, which can directly inhibit the proliferation of tumor cells, antagonize the carcinogenic effects of carcinogens and induce apoptosis by regulating cell cycle and activating endogenous and exogenous pathways. 25,26 Luteolin also has antitumor effects of invasion and metastasis, antitumor angiogenesis and chemotherapy sensitization effects. 27,28 The antitumor effect of luteolin involved complex signal transduction pathways and regulatory mechanisms.…”

Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

“…The abnormal high cytoplasmic calcium level could result in mitochondrial permeability transition pore opening, ΔΨm decrease, and finally cause apoptosis of cardiomyocytes [32]. In addition, Lut can regulate cell apoptosis by enhancing autophagy [33, 34]. These may be the mechanism involved in the protective effect of Lut on I/R cardiomyocytes.…”