Baicalein Represses Cervical Cancer Cell Growth, Cell Cycle Progression and Promotes Apoptosis via Blocking AKT/mTOR Pathway by the Regulation of circHIAT1/miR-19a-3p Axis

Abstract

Background: Baicalein has a significant anti-cancerous function in the treatment of cervical cancer (CC). Its functional mechanism regarding circular RNA (circRNA) hippocampus abundant transcript 1 (circHIAT1) and microRNA-19a-3p (miR-19a-3p) was explored in this research. Methods: CC cell viability and colony formation were determined using Cell Counting Kit-8 (CCK-8) and colony formation assay. Cell cycle progression and apoptosis were analyzed via flow cytometry. Protein markers of cell cycle, apoptosis and protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway were detected by Western blot. CircHIAT1 and miR-19a-3p levels were assayed through the quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between circHIAT1 and miR-19a-3p was validated by dual-luciferase reporter and RNA pull-down assays. In vivo experiment was performed by xenograft model. Results: CC cell growth and cell cycle progression were repressed while apoptosis was enhanced by baicalein. MiR-19a-3p was downregulated in baicalein-treated CC cells and miR-19a-3p overexpression lightened the baicalein-induced CC progression inhibition. Moreover, circHIAT1 was found to be a sponge of miR-19a-3p in CC cells. Baicaleininduced cell growth inhibition, cell cycle arrest and apoptosis promotion were neutralized by knockdown of circHIAT1 via targeting miR-19a-3p. Baicalein acted on the circHIAT1/miR-19a-3p to inactivate AKT/mTOR pathway. Baicalein also reduced CC tumor growth in vivo via regulating the levels of circHIAT1 and miR-19a-3p. Conclusion: These findings demonstrated that the inhibitory function of baicalein in CC progression was dependent on the repression of AKT/mTOR pathway by upregulating circHIAT1 to sponge miR-19a-3p, showing a specific mechanism for baicalein in CC.

Therapeutic Properties of Flavonoids in Treatment of Cancer through Autophagic Modulation: A Systematic Review

“…(20,21) Baicalein is a potential phytotherapic relevant in the treatment of tumors, in addition to being a compound with extremely low toxic effects-with actions that indicate a "hunt" for the tumor cells themselves, preserving healthy cells. (21) Its mechanisms have been studied in several types of tumors, including hepatocellular carcinoma, (22) cervical cancer, (23) breast, (24) prostate, (25) among others.…”

Regulation of Cell Signaling Pathways and Non-Coding RNAs by Baicalein in Different Cancers

“…Additionally, baicalein-mediated inactivation of the AKT/mTOR pathway has also been demonstrated in cervical cancer cells. Baicalein inactivated AKT and mTOR in cervical cancer cells through upregulation of circular RNA (circHIAT1) and inhibition of miR-19a-3p [ 66 ]. Importantly, baicalein induced shrinkage of the tumor mass in mice subcutaneously inoculated with circHIAT1-expressing HeLa cells.…”

“…Importantly, baicalein induced shrinkage of the tumor mass in mice subcutaneously inoculated with circHIAT1-expressing HeLa cells. However, baicalein-mediated tumor inhibition was partially reduced in mice inoculated with circHIAT1-silenced HeLa cells [ 66 ].…”

Potential Mechanisms of Plant-Derived Natural Products in the Treatment of Cervical Cancer

“…In addition, baicalein had strong anti-inflammatory activity by inhibiting the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and p38, which reduced the expression of the inflammatory cytokines, including interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP1) [22][23][24]. Moreover, baicalein inactivated the AKT/mammalian target of rapamycin (mTOR) pathway by targeting the circHIAT1/miR-19a-3p axis to inhibit the proliferation of cervical cancer cells [25]. Another study illustrated that baicalin significantly suppressed cervical cancer xenograft tumor growth and metastasis in vivo through intraperitoneally injecting 10 mg/kg/d baicalin for four weeks.…”