Ginsenoside Rh2 inhibits HeLa cell energy metabolism and induces apoptosis by upregulating voltage‑dependent anion channel 1

Liu, Ying; Wang, Jiawen; Qiao, Juhui; Liu, Shichao; Wang, Siming; Zhao, Daqing; Bai, Xueyuan; Liu, Meichen

doi:10.3892/ijmm.2020.4725

Cited by 12 publications

(17 citation statements)

References 56 publications

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“…HK1 and HK2 are known to be mitochondrial hexokinase isotypes because they participate in glucose metabolism by binding to mitochondria. They are mainly expressed in mitochondria, but there is also a small expression in the cytoplasm [ 5 , 6 , 7 ]. To study the expression of HK, we first studied the mRNA and overall protein levels of HK1 and HK2 using quantitative real-time PCR (Q-PCR) and Western blotting, respectively, in vivo and in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…A decreased expression of HK and dissociation from mitochondria reduces glucose metabolism, promotes mitochondrial dysfunction, and leads to a disruption of the NAD+/NADH ratio, the depolarization of membrane potential and the opening of mitochondrial permeability transition pores. It further promotes mitochondrial reactive oxygen species (ROS) release and NLRP3 inflammasome activation [ 7 , 8 , 9 , 10 , 11 , 12 ]. Consistently with these observations, we found decreased expression of HK and combination of it with mitochondria in N2a-sw cells.…”

Section: Discussionmentioning

confidence: 99%

“…There are four HK isozymes: HK1, HK2, HK3 and HK4. Among them, HK1 and HK2 are known to be associated with the mitochondrial outer membrane and expressed in the brain [ 5 , 6 , 7 ]. The mitochondrial-HK (mHK) participates in glucose metabolism and regulates the generation of reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Increased IL-1β on Expression of HK in Alzheimer’s Disease

Han

Jacob

et al. 2021

IJMS

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by decreased glucose metabolism and increased neuroinflammation. Hexokinase (HK) is the key enzyme of glucose metabolism and is associated with mitochondria to exert its function. Recent studies have demonstrated that the dissociation of HK from mitochondria is enough to activate the NOD-like receptor protein 3 (NLRP3) inflammasome and leads to the release of interleukin-1β (IL-1β). However, the effect of increased IL-1β on the expression of HK is still unclear in AD. In this paper, we used positron emission tomography (PET), Western blotting and immunofluorescence to study the glucose metabolism, and the expression and distribution of HK in AD. Furthermore, we used lipopolysaccharide (LPS), nigericin (Nig), CY-09 and lonidamine (LND) to treat N2a and N2a-sw cells to investigate the link between IL-1β and HK in AD. The results show decreased expression of HK and the dissociation of HK from mitochondria in AD. Furthermore, a reduction of the expression of IL-1β could increase the expression of HK in AD. These results suggest that inhibiting inflammation may help to restore glucose metabolism in AD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effect of Increased IL-1β on Expression of HK in Alzheimer’s Disease

Han

Jacob

et al. 2021

IJMS

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“…The presence of mitochondrial dysfunction was considered as a possible mechanism of G-Rh2-induced cytotoxicity (36). A previous study by our group suggested that G-Rh2 upregulated voltage-dependent anion channel 1 to trigger the mitochondrial translocation of BAX, promoting cytochrome c release and initiating mitochondrial-dependent apoptosis in HeLa cells (24). In the present study, it was revealed that the effect of G-Rh2 on the dissipation of the MMP and the reduction in ATP generation in HeLa cells was much stronger than that in C33A cells, consistent with the cell viability and apoptosis results.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rh2 stimulates the production of mitochondrial reactive oxygen species and induces apoptosis of cervical cancer cells by inhibiting mitochondrial electron transfer chain complex

Liu

Xing

et al. 2021

Mol Med Rep

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Ginsenoside Rh2 (G-Rh2) is a monomeric compound that extracted from ginseng and possesses anti-cancer activities both in vitro and in vivo . Previously, we reported that G-Rh2 induces apoptosis in HeLa cervical cancer cells and that the process was related to reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. However, the upstream mechanisms of G-Rh2, along with its cellular targets, remain to be elucidated. In the present study, the Cell Counting Kit-8 assay, flow cytometry and Hoechst staining revealed that G-Rh2 significantly inhibited cell viability and induced apoptosis of cervical cancer cells. However, G-Rh2 was demonstrated to be non-toxic to End1/e6e7 cells. JC-1, rhodamine 123 staining, oxidative phosphorylation and glycolysis capacity assays demonstrated that G-Rh2 exposure caused an immediate decrease in mitochondrial transmembrane potential due to its inhibition of mitochondrial oxidative phosphorylation, as well as glycolysis, both of which reduced cellular ATP production. Western blotting and electron transport chain (ETC) activity assays revealed that G-Rh2 significantly inhibited the activity of ETC complexes I, III and V. Overexpression of ETC complex III partially significantly restored mitochondrial ROS and inhibited the apoptosis of cervical cancer cells induced by G-Rh2. The predicted results of binding energy in molecular docking, confirmed that G-Rh2 was highly likely to induce mitochondrial ROS production and promote cell apoptosis by targeting the ETC complex, especially for ETC complex III. Taken together, the present results revealed the potential anti-cervical cancer activity of G-Rh2 and provide direct evidence for the contribution of impaired ETC complex activity to cervical cancer cell death.

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“…Ginsenoside Rh2 activated mitochondriadependent apoptosis pathway and inhibited mitochondrial oxidative phosphorylation and glycolysis in HeLa cells. In addition, ginsenoside Rh2 inhibited energy metabolism and induced apoptosis in HeLa cells by upregulating voltage-dependent anion channel 1 (VDAC1), which caused MMP depolarization and ROS production [145]. It is suggested that VDAC1 is a new target of ginsenoside Rh2.…”

Section: Diterpenoids and Terperpenoidsmentioning

confidence: 99%

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

2021

Biomolecules

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Cervical cancer is the second most common gynecological malignancy globally; it seriously endangers women’s health because of its high morbidity and mortality. Conventional treatments are prone to drug resistance, recurrence and metastasis. Therefore, there is an urgent need to develop new drugs with high efficacy and low side effects to prevent and treat cervical cancer. In recent years, plant-derived natural products have been evaluated as potential anticancer drugs that preferentially kill tumor cells without severe adverse effects. A growing number of studies have shown that natural products can achieve practical anti-cervical-cancer effects through multiple mechanisms, including inhibition of tumor-cell proliferation, induction of apoptosis, suppression of angiogenesis and telomerase activity, enhancement of immunity and reversal of multidrug resistance. This paper reviews the therapeutic effects and mechanisms of plant-derived natural products on cervical cancer and provides references for developing anti-cervical-cancer drugs with high efficacy and low side effects.

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Ginsenoside Rh2 inhibits HeLa cell energy metabolism and induces apoptosis by upregulating voltage‑dependent anion channel 1

Cited by 12 publications

References 56 publications

Effect of Increased IL-1β on Expression of HK in Alzheimer’s Disease

Effect of Increased IL-1β on Expression of HK in Alzheimer’s Disease

Ginsenoside Rh2 stimulates the production of mitochondrial reactive oxygen species and induces apoptosis of cervical cancer cells by inhibiting mitochondrial electron transfer chain complex

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

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