Luteoloside Inhibits Proliferation and Promotes Intrinsic and Extrinsic Pathway-Mediated Apoptosis Involving MAPK and mTOR Signaling Pathways in Human Cervical Cancer Cells

Abstract

Cervical cancer is a common gynecological malignancy with high incidence and mortality. Drugs commonly used in chemotherapy are often accompanied by strong side-effects. To find an anti-cervical cancer drug with high effects and low toxicity, luteoloside was used to treat the cervical cancer cell line Hela to investigate its effects on cell morphology, proliferation, apoptosis, and related proteins. The study demonstrated that luteoloside could inhibit proliferation remarkably; promote apoptosis and cytochrome C release; decrease the mitochondrial membrane potential and reactive oxygen species level; upregulate the expression of Fas, Bax, p53, phospho-p38, phospho-JNK, and cleaved PARP; downregulate the expression of Bcl-2 and phospho-mTOR; activate caspase-3 and caspase-8; change the nuclear morphology, and fragmentate DNA in Hela cells. These results strongly suggest that luteoloside can significantly inhibit the proliferation and trigger apoptosis in Hela cells. In contrast, luteoloside had less proliferation inhibiting effects on the normal cell lines HUVEC12 and LO2, and minor apoptosis promoting effects on HUVEC12 cells. Furthermore, the luteoloside-induced apoptosis in Hela cells is mediated by both intrinsic and extrinsic pathways and the effects of luteoloside may be regulated by the mitogen-activated protein kinases and mTOR signaling pathways via p53.

Systematic re‑analysis strategy of serum indices identifies alkaline phosphatase as a potential predictive factor for cervical cancer

“…Recently, evidence indicated that TNALP could regulate cranial base growth and synchondrosis maturation via mitogen-activated protein kinase (MAPK) signalling (24). Previous studies have also indicated the role of MAPK signaling in tumorigenesis (25–28), and demonstrated that oncogenes promote tumor growth and metastasis through the MAPK signaling pathway (29). Ectopic activation of the MAPK signaling pathway enhances the progression of cancer (30).…”

Luteoloside Exerts Analgesic Effect in a Complete Freund’s Adjuvant-Induced Inflammatory Model via Inhibiting Interleukin-1β Expression and Macrophage/Microglia Activation

“…Some reports have found that luteoloside and celecoxib both have COX-2-independent effects on the signal pathways, such as MAPK/p38, and ERK. (Wu et al, 2004;Hua et al, 2005;Ha et al, 2006;Kadam et al, 2007;Park et al, 2010;Wang et al, 2013;Akram et al, 2015;Jeon et al, 2015;Li et al, 2019;Shao et al, 2018). Although these results have not been applied to studies about analgesic effects, these mechanisms may be the reason of the synergistic effect in the acute analgesic role due to the critical role of MAPK/p38 and ERK signal pathways in the pain regulation.…”

“…Besides, recent studies found Glossogyne tenuifolia extract attenuates inflammatory mediator synthesis partly through down-regulating NF-κB activation ( Wu et al., 2004 ; Ha et al., 2006 ). What is more, luteoloside can inhibit cell proliferation via mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways ( Shao et al., 2018 ). The anti-inflammatory effect of luteoloside and its effects on pain-related signaling pathways indicate its application prospect in chronic inflammatory pain.…”

Natural Compounds and Derivatives as Ser/Thr Protein Kinase Modulators and Inhibitors

“…Luteolin is a type of flavonoid that inhibits proliferation involving MAPK and mTOR signalling pathways in various tumour cell lines [41].…”