Rosmarinic Acid Induces Proliferation Suppression of Hepatoma Cells Associated with NF-κB Signaling Pathway

Abstract

Background: Rosmarinic acid (RA) is a natural phenolic compound that acts as a Fyn inhibitor by 53 homology modeling of the human Fyn structure. Therefore, the apoptosis mechanism related to NF-κB signaling pathway induced by RA in HepG2 was investigated. Methods: The cell growth, apoptosis, and proliferation of HepG2 regulated by various concentrations of RA were studied. The proteins expression of MMP-2, MMP-9, PI3K, AKT, NF-κB, and apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3 were detected. Results: RA significantly reduced proliferation rates, inhibited migration and invasion, and decreased the expressions of invasion-related factors, such as matrix metalloproteinase (MMP)-2 and MMP-9. TUNEL staining revealed that RA resulted in a dose-dependent increase of HepG2 cell apoptosis. In line with this finding, the expression of apoptosis suppressor protein Bcl-2 was downregulated and that of the pro-apoptotic proteins Bax and cleaved caspase-3 was increased. In addition, we found that the phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor kappa B (NF-κB) signaling pathway was involved in RA-mediated inhibition of HepG2 cell metastasis. Conclusion: Our study identified that RA as a drug candidate for the treatment of HCC.

Rosmarinic Acid and Related Dietary Supplements: Potential Applications in the Prevention and Treatment of Cancer

“…PI3K/AKT is the primary pathway of RA-mediated apoptosis. In treating HCC and glioma, RA acted as a Fyn inhibitor, promoting the expression of apoptosis-related proteins through the PI3K/AKT and NF-κB pathways [ 10 , 109 ]. RA downregulated the PI3K/AKT/the mechanistic target of rapamycin (mTOR) signaling pathway to induce apoptosis and inhibited epithelial-mesenchymal transition (EMT) and tumor growth in HCC and osteosarcoma [ 108 , 110 ].…”

“…RA inhibited the expression of MMP-2 and MMP-9 and cell invasive ability in several tumor cell lines and attenuated lung metastasis of CRC in a mouse model [ 60 , 100 , 107 ]. The downregulation of MMP-2 and MMP-9 by RA as a Fyn inhibitor in treating HCC and glioma suppressed tumor invasion and migration [ 10 , 109 ]. Downregulation of AKT phosphorylation with repression by MMPs contributed to the suppression of tumor invasion ability [ 101 , 108 ].…”

“…RA was shown to possess a wide range of applications in the treatment of HCC, including induction of apoptosis, and inhibition of tumor growth and metastasis. Meanwhile, RA demonstrated little effects on the proliferation and morphology of normal human astrocytes cells [ 109 ]. Treatment of RA mediated the upregulation of caspase-3, -8, and -9 and inhibited BCL-2 expression to induce apoptosis in different HCC cell lines [ 19 , 106 ].…”

“…Treatment of RA mediated the upregulation of caspase-3, -8, and -9 and inhibited BCL-2 expression to induce apoptosis in different HCC cell lines [ 19 , 106 ]. The downregulation of PI3K/AKT and glycolytic pathway by RA inhibited the cell proliferation and tumor growth of HCC [ 109 , 110 , 123 ]. Furthermore, RA analogue-11 is a synthesized RA analogue, which promoted apoptosis via the EGFR/AKT/NF-κB pathway in gastric cancer cells [ 142 ].…”

The pathogenesis of liver cancer and the therapeutic potential of bioactive substances

“…RA can inhibit the expression of Fyn in HepG2 hepatoma cells, as well as the proliferation, migration, and invasion of hepatoma cells, and the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in a dose-dependent manner. It increased the expression of cleaved caspase-3 and the pro-apoptotic protein Bax, down-regulated the expression of the apoptosis inhibitory protein Bcl-2 in a dose-dependent manner and promoted the apoptosis of liver cancer cells, reducing the expression levels of PI3K, p-Akt, and NF-κB proteins ( An et al, 2021 ).…”