Ginsenoside Rk1 regulates glutamine metabolism in hepatocellular carcinoma through inhibition of the ERK/c-Myc pathway

Lu, Haoping; Yin, Huayu; Liu, Qu; Ma, Xiaoxuan; Fu, Rongzhan; Fan, Daidi

doi:10.1039/d1fo03728e

Cited by 15 publications

(10 citation statements)

References 60 publications

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“…These events are also relevant to Ginsenoside Rg3 treatment, which disrupts the biological functions of ZFP91 [ 539 ]. The ginsenoside Rk1 alters c-MYC, which engages in cross-talk with ERK during glutamine metabolism, and exerts anti-cancer activity with lower cytotoxicity than sorafenib [ 540 ]. Other ginsenosides, including Rg1, Rh4, and Rg5, with specific structures and functions, can inhibit cancers accompanied by suppression of c-MYC, indicating that bio-modulators induced by these natural homologs have common features [ 541 ].…”

Section: Myc Modulators As Cancer Treatmentsmentioning

confidence: 99%

MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products

Chan,

Zhang,

et al. 2024

Aging and disease

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Various diseases, including cancers, age-associated disorders, and acute liver failure, have been linked to the oncogene, MYC . Animal testing and clinical trials have shown that sustained tumor volume reduction can be achieved when MYC is inactivated, and different combinations of therapeutic agents including MYC inhibitors are currently being developed. In this review, we first provide a summary of the multiple biological functions of the MYC oncoprotein in cancer treatment, highlighting that the equilibrium points of the MYC/MAX, MIZ1/MYC/MAX, and MAD (MNT)/MAX complexes have further potential in cancer treatment that could be used to restrain MYC oncogene expression and its functions in tumorigenesis. We also discuss the multifunctional capacity of MYC in various cellular cancer processes, including its influences on immune response, metabolism, cell cycle, apoptosis, autophagy, pyroptosis, metastasis, angiogenesis, multidrug resistance, and intestinal flora. Moreover, we summarize the MYC therapy patent landscape and emphasize the potential of MYC as a druggable target, using herbal medicine modulators. Finally, we describe pending challenges and future perspectives in biomedical research, involving the development of therapeutic approaches to modulate MYC or its targeted genes. Patients with cancers driven by MYC signaling may benefit from therapies targeting these pathways, which could delay cancerous growth and recover antitumor immune responses.

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Section: Myc Modulators As Cancer Treatmentsmentioning

confidence: 99%

MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products

Chan,

Zhang,

et al. 2024

Aging and disease

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“…Moreover, reducing glutamine intake in TCA results in the reduction of NADPH, which serves as GSH biosynthesis ( Jin et al, 2020 ). Ginsenoside Rk1 demonstrates anti-tumor effectiveness by downregulating GLS1, decreasing GSH, and subsequently accumulating ROS ( Lu et al, 2022 ); and there are two clinical trials that use Ginsenoside in hepatocellular carcinoma(NCT01717066, NCT04523467). Dihydroartemisinin (DHA) induces oxidative stress in cancer cells by increasing intracellular reactive oxygen species (ROS).…”

Section: Glutamine Metabolism Targeting Therapymentioning

confidence: 99%

Glutamine metabolic reprogramming in hepatocellular carcinoma

Ye,

Yu,

Wang

et al. 2023

Front. Mol. Biosci.

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Hepatocellular carcinoma (HCC) is a lethal disease with limited management strategies and poor prognosis. Metabolism alternations have been frequently unveiled in HCC, including glutamine metabolic reprogramming. The components of glutamine metabolism, such as glutamine synthetase, glutamate dehydrogenase, glutaminase, metabolites, and metabolite transporters, are validated to be potential biomarkers of HCC. Increased glutamine consumption is confirmed in HCC, which fuels proliferation by elevated glutamate dehydrogenase or upstream signals. Glutamine metabolism also serves as a nitrogen source for amino acid or nucleotide anabolism. In addition, more glutamine converts to glutathione as an antioxidant in HCC to protect HCC cells from oxidative stress. Moreover, glutamine metabolic reprogramming activates the mTORC signaling pathway to support tumor cell proliferation. Glutamine metabolism targeting therapy includes glutamine deprivation, related enzyme inhibitors, and transporters inhibitors. Together, glutamine metabolic reprogramming plays a pivotal role in HCC identification, proliferation, and progression.

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“…Furthermore, c-Myc can bind to the E-box on the nuclear factor E2-related factor 2 ( NRF2 ) promoter to activate NRF2 transcription, thereby maintaining intracellular redox homeostasis ( 29 ). The non-transcription factor activities of c-Myc have also been identified; for example, c-Myc has been found to be able to directly inhibit the expression of miR-23b, which regulates cellular ferroptosis by targeting glutaminase expression at the 3′-untranslated region (3′-UTR) ( 30 , 31 ). c-Myc was also demonstrated to directly bind and inhibit nuclear receptor coactivator 4 ( NCOA4 ) mRNA expression, suppressing ferroptosis by inhibiting ferritinophagy ( 32 ).…”

Section: Celf2 Affects Ferroptosis Through the Mapk Signalling Pathwaymentioning

confidence: 99%

Role of CELF2 in ferroptosis: Potential targets for cancer therapy (Review)

Zhu

et al. 2023

Int J Mol Med

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Ferroptosis is a novel form of regulated cellular necrosis that plays a critical role in promoting cancer progression and developing drug resistance. The main characteristic of ferroptosis is iron-dependent lipid peroxidation caused by excess intracellular levels of reactive oxygen species. CUGBP ELAV-like family number 2 (CELF2) is an RNA-binding protein that is downregulated in various types of cancer and is associated with poor patient prognoses. CELF2 can directly bind mRNA to a variety of ferroptosis control factors; however, direct evidence of the regulatory role of CELF2 in ferroptosis is currently limited. The aim of the present review was to summarise the findings of previous studies on CELF2 and its role in regulating cellular redox homeostasis. The present review may provide insight into the possible mechanisms through which CELF2 affects ferroptosis and to provide recommendations for future studies.

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Ginsenoside Rk1 regulates glutamine metabolism in hepatocellular carcinoma through inhibition of the ERK/c-Myc pathway

Abstract: Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers in the world. Recently, suppression glutamine metabolism becomes one of the hottest therapy targets for cancer treatment. There...

Cited by 15 publications

References 60 publications

MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products

MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products

Glutamine metabolic reprogramming in hepatocellular carcinoma

Role of CELF2 in ferroptosis: Potential targets for cancer therapy (Review)

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