Puerarin Induces Hepatocellular Carcinoma Cell Apoptosis Modulated by MAPK Signaling Pathways in a Dose-dependent Manner

Zhang, Weiguo; Yin, Xiu-Cai; Liu, Xiaofang; Meng, Kewei; Tang, Kun; Huang, Fei-Long; Xu, Gang; Gao, Jie

doi:10.21873/anticanres.11837

Cited by 10 publications

(8 citation statements)

References 27 publications

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“…But in other research, Puerarin inhibited proliferation of SMMC-7721 cells and promoted their apoptosis in a dose- and time-dependent fashion (p < 0.05). Both the expression and phosphorylation levels of MAPK proteins were dramatically increased on puerarin treatment 38 . However, in our study, MAP3K2 and PBX3 could promote HepG2 and SMMC-7721 cells proliferation and inhibit cells apoptosis rate partially through achieving phosphorylation levels of MAPK proteins.…”

Section: Discussionmentioning

confidence: 97%

miR-302a inhibits human HepG2 and SMMC-7721 cells proliferation and promotes apoptosis by targeting MAP3K2 and PBX3

Wang

Jiang

et al. 2019

Sci Rep

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Hepatocellular carcinoma (HCC) is the most common liver cancer and has a poor prognosis. miR-302a is an important regulator of tumor occurrence and deterioration, while MAP3K2 and PBX3 genes are involved in cancer cell proliferation and apoptosis. In this study, the expression of miR-302a and MAP3K2/PBX3 were evaluated by qPCR in liver cancer cell lines. Next, the target relationship between miR-302a and MAP3K2/PBX3 was verified using luciferase assays. Meanwhile, the expression correlation between miR-302a and target genes was analyzed in cancer tissue and para-cancerous tissue. In addition, an increased miR-302a level in HepG2 cells and SMMC-7721 cells were achieved through transfection with miR-302a mimics, and the effects on HepG2 cell and SMMC-7721 cell proliferation, apoptosis and MAPK pathways were determined using MTT, flow cytometry, qPCR and western blot assays. The results showed that liver cancer cell lines exhibited low miR-302a expression and MAP3K2 and PBX3 were confirmed to be the target genes of miR-302a. Meanwhile, the HE results showed that cells became enlarged with loose cytoplasm and formed balloon-like lesions in HCC specimens and we found a significant negative correlation between miR-302a and MAP3K2/PBX3 expression. In addition, treatment with miR-302a mimics inhibited HepG2 cells and SMMC-7721 cells proliferation and increased the apoptosis rate. Further research revealed that the MAPK key factors p-p38, p-ERK1/2 and p-JNK were significantly reduced in miR-302a transfected cells and MAP3K2/PBX3 silenced cells. Besides, MAP3K2 and PBX3 overexpression in miR-302a mimics-treated cells exerted the opposite effects. In conclusion, miR-302a inhibited proliferation and promoted apoptosis in human hepatoma cells by targeting MAP3K2 and PBX3.

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Section: Discussionmentioning

confidence: 97%

miR-302a inhibits human HepG2 and SMMC-7721 cells proliferation and promotes apoptosis by targeting MAP3K2 and PBX3

Wang

Jiang

et al. 2019

Sci Rep

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“…82,83 NPs trigger the death of cancer cells through the MAPK/ERK pathway. 84 Pue induces apoptosis in SMMC7721 43,85 cells through ROS 43 -mediated p-38 MAPK 85 and ERK1 43 activation. 43,85 In NSCLC cells, Pue inhibits the IL-4-induced activation of MEK and ERK1/2 and its nuclear translocation.…”

Section: Mapk/erk (Ras-raf-mek-erk) Pathwaymentioning

confidence: 97%

“…84 Pue induces apoptosis in SMMC7721 43,85 cells through ROS 43 -mediated p-38 MAPK 85 and ERK1 43 activation. 43,85 In NSCLC cells, Pue inhibits the IL-4-induced activation of MEK and ERK1/2 and its nuclear translocation. 86 In addition, Pue reverses the oxidized low-density lipoprotein (ox-LDL)-induced increase in VSM cell proliferation through ERK1/2 and proliferating cell nuclear antigen activation, 87 as depicted in Table 1 and Figure 2.…”

Section: Mapk/erk (Ras-raf-mek-erk) Pathwaymentioning

confidence: 97%

<p>Molecular Mechanisms of Anticancer Activities of Puerarin</p>

Ahmad¹,

Khan²,

Liu³

et al. 2020

CMAR

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Medicinal plants are a vital source of natural products (NPs) that can cure cancer through modulation of different pathways, including oxidative stress, extrinsic and intrinsic apoptosis, cell cycle, inflammation, NF-kB, PI3K/AKT/mTOR, AMPK (JNK), MEK/ERK (Raf)-MEK-ERK and autophagy. Puerarin (Pue), an important NP belonging to the isoflavone glycoside group, is derived from Pueraria lobata (Willd.) Ohwi, Pueraria thomsonii Benth, and Pueraria tuberosa (Willd.). This NP was approved by the Chinese Ministry of Health for the treatment of different diseases in 1993, but it was also later reported to exhibit anticancer activity. Pue causes cancer cells death through modulation of different mechanisms including oxidative stress, intrinsic and extrinsic, Survivin and XIAP, PI3K/AKT/ mTOR, Ras-Raf-MEK-ERK, JNK, cell cycle, AMPK, NF-kB, inflammation and autophagy pathways. Therefore, this review compiles for the first time the studies about the anticancer mechanism of Pue and provides comprehensive information about the anticancer effects of Pue. This review may serve as a basis for future research and clinical treatment.

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“…In this class of phytochemicals, puerarin ( Figure 4 A) act as a protective agent against ROS-induced apoptosis by decreasing Bax/Bcl-2 ratio and apoptosis, as well as preventing neuronal disorders such as Alzheimer’s disease [ 107 ] and PC12 cancer cells [ 56 ]. Puerarin treatment of HCC cell lines increased the phosphorylation and activation of MAPK and act as an anticancer agent by exhibiting pro-apoptotic activities [ 108 ]. Combinatorial treatment of genistein and hypericin ( Figure 4 A) in human breast cancer cells resulted in the reduction of Bcl-2 expression while an increase in Bax expression suppressed Akt and ERK1/2 phosphorylation [ 57 ].…”

Section: Bcl-2 Inhibition Passes Through the P53 Pathway By Flavonoidsmentioning

confidence: 99%

“…In human breast cancer cells, delphinidin ( Figure 5 B) treatment inhibited cell proliferation by blocking the Akt signaling pathway and inducing apoptosis by increasing Bcl-2 expression along with increasing Bax expression in a dose-dependent manner [ 75 ]. Bilberry extract ( Figure 5 B) (which contain delphinidin-3-O-glucoside, cyanidin-3-O-glucoside, delphinidin-3-O-rutinoside, cyanidin-3-O-galactoside, and cyanidin-3-O-rutinoside flavonoids) was applied to chronic lymphocytic leukemia which activated caspase-3, de-phosphorylated Akt and inhibited Bcl-2 and resulted in the induction of apoptosis [ 108 ]. Procyanidins B and procyanidin C ( Figure 5 B) are formed from the oligomers of catechin and epicatechin.…”

Section: Bcl-2 Inhibition Passes Through the P53 Pathway By Flavonoidsmentioning

confidence: 99%

Bcl-2 Modulation in p53 Signaling Pathway by Flavonoids: A Potential Strategy towards the Treatment of Cancer

Rahman

Khan

Zia

et al. 2021

IJMS

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Cancer is a major cause of death, affecting human life in both developed and developing countries. Numerous antitumor agents exist but their toxicity and low efficacy limits their utility. Furthermore, the complex pathophysiological mechanisms of cancer, serious side effects and poor prognosis restrict the administration of available cancer therapies. Thus, developing novel therapeutic agents are required towards a simultaneous targeting of major dysregulated signaling mediators in cancer etiology, while possessing lower side effects. In this line, the plant kingdom is introduced as a rich source of active phytochemicals. The secondary metabolites produced by plants could potentially regulate several dysregulated pathways in cancer. Among the secondary metabolites, flavonoids are hopeful phytochemicals with established biological activities and minimal side effects. Flavonoids inhibit B-cell lymphoma 2 (Bcl-2) via the p53 signaling pathway, which is a significant apoptotic target in many cancer types, hence suppressing a major dysregulated pathway in cancer. To date, there have been no studies reported which extensively highlight the role of flavonoids and especially the different classes of flavonoids in the modulation of Bcl-2 in the P53 signaling pathway. Herein, we discuss the modulation of Bcl-2 in the p53 signaling pathway by different classes of flavonoids and highlight different mechanisms through which this modulation can occur. This study will provide a rationale for the use of flavonoids against different cancers paving a new mechanistic-based approach to cancer therapy.

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Puerarin Induces Hepatocellular Carcinoma Cell Apoptosis Modulated by MAPK Signaling Pathways in a Dose-dependent Manner

Abstract: Puerarin could be employed as a potential anti-carcinogen that exhibits pro-apoptotic effects on HCC cells, in a dose- and time-dependent manner, with emphasis on MAPK pathways whose initiation may contribute to this process.

Cited by 10 publications

References 27 publications

miR-302a inhibits human HepG2 and SMMC-7721 cells proliferation and promotes apoptosis by targeting MAP3K2 and PBX3

miR-302a inhibits human HepG2 and SMMC-7721 cells proliferation and promotes apoptosis by targeting MAP3K2 and PBX3

<p>Molecular Mechanisms of Anticancer Activities of Puerarin</p>

Bcl-2 Modulation in p53 Signaling Pathway by Flavonoids: A Potential Strategy towards the Treatment of Cancer

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