[6]‐Gingerol–induced cell cycle arrest, reactive oxygen species generation, and disruption of mitochondrial membrane potential are associated with apoptosis in human gastric cancer (AGS) cells

Mansingh, Debjani P.; Sunanda, O J; Sali, Veeresh Kumar; Vasanthi, Hannah R.

doi:10.1002/jbt.22206

Cited by 47 publications

(32 citation statements)

References 24 publications

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“…Our studies showed that upregulation of SOD2 maintains mitochondrial function, indicated by reduction in mitochondrial ATP production and MMP in SOD2 knockdown CRC cells. Such protection through maintaining mitochondrial integrity was previously reported in other cancer types 38 . Enhanced glycolysis is also a common characteristic in the majority of malignant tumors.…”

Section: Discussionsupporting

confidence: 71%

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Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK‐mediated energy metabolism

Zhou

Lyu

Miao

et al. 2020

Molecular Carcinogenesis

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Colorectal cancer (CRC) is a common malignancy. Many reports have implicated aberrant mitochondrial activity in the progression of CRC, with particular emphasis on the dysregulation of redox signaling and oxidative stress. In this study, we focused on manganese superoxide dismutase (MnSOD/SOD2), a key antioxidant enzyme, which maintains intracellular redox homeostasis. Current literature presents conflicting mechanisms for how SOD2 influences tumorigenesis and tumor progression. Here, we explored the role of SOD2 in CRC specifically. We found high levels of SOD2 expression in CRC tissues. We carried out a series of experiments to determine whether knockdown of SOD2 expression in CRC cell lines would reverse features of tumorigenesis. We found that reduced SOD2 expression decreased cell proliferation, migration, and invasion activity in CRC cells. Results from an additional series of experiments on mitochondrial function implicated a dual role for SOD2 in promoting CRC progression. First, proper level of SOD2 helped CRC cells maintain mitochondrial function by disposal of superoxide (O2.−). Second, over‐expression of SOD2 induced H2O2‐mediated tumorigenesis by upregulating AMPK and glycolysis. Our results indicate that SOD2 may promote the occurrence and development of CRC by regulating the energy metabolism mediated by AMPK signaling pathways.

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Section: Discussionsupporting

confidence: 71%

“…Such protection through maintaining mitochondrial integrity was previously reported in other cancer types. 38 Enhanced glycolysis is also a common characteristic in the majority of malignant tumors. Our study provided a link between enhanced SOD2 expression and increased glycolytic activity.…”

Section: Regulation Of Energy Metabolism In Crcmentioning

confidence: 99%

Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK‐mediated energy metabolism

Zhou

Lyu

Miao

et al. 2020

Molecular Carcinogenesis

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“…Although ginger used as a herbal medicine or seasoning has been shown consistent effects of promoting mitochondrial function (Misawa et al., ; Oh et al., ), studies suggested varying conclusions in the effects of its components including 6‐gingerol and 6‐shogaol on mitochondrial function. It was reported that 6‐gingerol attenuated oxidative damage on cell death of neurons (Lee, Park, Kim, & Jang, ), while it damaged the mitochondrial function resulting in cellular apoptosis in several other cell types (Mansingh, O J, Sali, & Vasanthi, ; Nigam, Bhui, Prasad, George, & Shukla, ; Yang et al., ). 6‐Shogaol was consistently reported to damage mitochondrial function of cells (Annamalai, Kathiresan, & Kannappan, ; Chen et al., ; Warin, Chen, Soroka, Zhu, & Sang, ).…”

Section: Discussionmentioning

confidence: 99%

Promotion of Mitochondrial Biogenesis via Activation of AMPK‐PGC1ɑ Signaling Pathway by Ginger (Zingiber officinale Roscoe) Extract, and Its Major Active Component 6‐Gingerol

Deng

Zhang

et al. 2019

Journal of Food Science

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Several studies indicated that ginger (Zingiber officinale Roscoe) enhances thermogenesis and/or energy expenditure with which to interpret the beneficial effects of ginger on metabolic disorders. It is well known that mitochondrial activity plays an essential role in these processes. Thus, this study aimed to investigate the effect of ginger extract (GE) and its major components, 6‐gingerol and 6‐shogaol, on mitochondrial biogenesis and the underlying molecular mechanisms. Our results showed that GE at dose of 2 g/kg promoted oxygen consumption and intrascapular temperature in mice. The mitochondrial DNA (mtDNA) copy number in muscle and liver increased. Expression levels of oxidative phosphorylation (OXPHOS) related proteins and AMP‐activated protein kinase ɑ/proliferator‐activated receptor gamma coactivator 1 ɑ (AMPK/PGC1ɑ) signaling related proteins in the muscle, liver, and brown adipose tissue (BAT) increased as well. In HepG2 cells, GE at concentration of 2.5 and 5 mg/mL increased mitochondrial mass and mtDNA copy number. GE promoted ATP production, the activities of mitochondrial respiratory chain complex I and IV, and expression levels of OXPHOS complex related proteins and AMPK/PGC1ɑ signaling related proteins. The antagonist of AMPK eliminated partly the effect of GE on mitochondrial biogenesis. 6‐Gingerol increased mitochondrial mass, mtDNA copy number and ATP production, and the activities of mitochondrial respiratory chain complexes in HepG2 cells as well. However, both 6‐gingerol at high concentration of 200 µM and 6‐shogaol at 10 to 200 µM inhibited cell viability. In conclusion, GE promoted mitochondrial biogenesis and improved mitochondrial functions via activation of AMPK‐PGC1ɑ signaling pathway, and 6‐gingerol other than 6‐shogaol, may be the main active component. Practical Application Ginger (Zingiber officinale Roscoe) is a food seasoning and also used as a medical plant in alternative medicine throughout the world. Here, we demonstrated that ginger extract (GE) promoted mitochondrial biogenesis and mitochondrial function via activation of AMPK‐PGC1ɑ signaling pathway both in mice and in HepG2 cells, and 6‐gingerol may be its main active component. Ginger, with anticipated safety, is expected to be a long‐term used dietary supplement and be developed into a new remedy for mitochondrial dysfunctional disorders.

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“…6-Gingerol has been previously shown to inhibit tumor cell growth through downregulation of cell-cycle regulators CDK1, cyclin A, and cyclin B1 and by repressing cyclin D1 in colorectal cancer cells [24], by activating caspases 3 and 9 and modulating mitochondrial functions in human gastric cancer cells [11], by inhibiting protein expression of the cyclin family and mTOR pathway in human cervical adenocarcinoma cells [15], by decreasing cyclin A and CDK expression, and by altering MAPK and PI3K-AKT pathways in pancreatic cancer cells [12]. The previous research results have indicated that the AKT-GSK 3β pathway and cyclins may be the common mechanism of action of 6-gingerol in its antitumor activities.…”

Section: Discussionmentioning

confidence: 99%

“…6-Gingerol, 1-[4′-hydroxy-3′-methoxyphenyl]-5-hydroxy-3-decanone, is a major pharmacologically active ingredient of ginger [9,10]. Compared to 6-shogaol, 8-gingerol, and 10-gingerol (three other phytochemicals in ginger), 6-gingerol is reported to exert a wide array of biochemical and pharmacological actions, including antibacterial, anti-inflammatory, antioxidant, and antitumor capabilities [11][12][13][14][15][16]. Evidence has shown, for example, that 6-gingerol can induce cell-cycle G2-phase arrest and apoptosis by activating caspases 3 and 7 in oral and cervical tumor cells [17], stimulate autophagy via drug-DNA interaction and caspase-3-mediated apoptosis in HeLa cells [16], inhibit cell proliferation though mitogen-activated protein kinase (MAPK)activator protein 1 (AP-1) signaling in colon cancer [13], and suppress metastasis in breast cancer [18].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

6-Gingerol induces cell-cycle G1-phase arrest through AKT–GSK 3β–cyclin D1 pathway in renal-cell carcinoma

Zhang

Liu

et al. 2019

Cancer Chemother Pharmacol

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Purpose 6-Gingerol, a major biochemical and pharmacological active ingredient of ginger, has shown anti-inflammatory and antitumor activities against various cancers. Searching for natural products with fewer side effects for developing adjunctive therapeutic options is necessary. Methods The effects of 6-gingerol on proliferation, colony formation, and cell cycle in RCC cells were detected by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and propidium iodide (PI) staining, respectively. Western blotting, an immunofluorescence assay, and immunohistochemical staining were performed to assess the expression of relevant proteins. A subcutaneous tumor model was set up to investigate the 6-gingerol effects on tumor growth in vivo, and the pharmacokinetics of 6-gingerol in mice were detected by LC/MS assays. Results 6-Gingerol treatment exerted time-and dose-dependent inhibition of the growth and colony formation of ACHN, 786-O, and 769-P cells, leading to a concomitant induction of cell-cycle G1-phase arrest and decrease in Ki-67 expression in the cell nucleus. Western-blotting results showed that 6-gingerol reduces phosphorylation of protein kinase B (AKT) Ser 473, cyclin-dependent kinases (CDK4), and cyclin D1 and, meanwhile, increases glycogen synthase kinase (GSK 3β) protein amount. Furthermore, the efficacy of 6-gingerol was demonstrated in an in vivo murine model of 786-O. Conclusion The above results indicate that 6-gingerol can induce cell-cycle arrest and cell-growth inhibition through the AKT-GSK 3β-cyclin D1 signaling pathway in vitro and in vivo, suggesting that 6-gingerol should be useful for renal-cell carcinoma treatment.

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[6]‐Gingerol–induced cell cycle arrest, reactive oxygen species generation, and disruption of mitochondrial membrane potential are associated with apoptosis in human gastric cancer (AGS) cells

Cited by 47 publications

References 24 publications

Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK‐mediated energy metabolism

Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK‐mediated energy metabolism

Promotion of Mitochondrial Biogenesis via Activation of AMPK‐PGC1ɑ Signaling Pathway by Ginger (Zingiber officinale Roscoe) Extract, and Its Major Active Component 6‐Gingerol

6-Gingerol induces cell-cycle G1-phase arrest through AKT–GSK 3β–cyclin D1 pathway in renal-cell carcinoma

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