The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma

Zhang, Xuan; Yang, Hua; Yue, Shu-Qiang; He, Guangbin; Qu, Shibin; Zhang, Zhuochao; Ma, Ben; Ding, Rui; Peng, Wei; Zhang, Hongtao; Yang, Zhao-Xu; Dou, Kefeng; Tao, Kaishan; Li, Xiao

doi:10.1002/cam4.1127

Cited by 33 publications

(28 citation statements)

References 41 publications

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“…Evidence has confirmed that RAD001 can substantially induce autophagy, as well as promote the apoptosis of breast cancer cells 22 and hepatocellular carcinoma cells. 23 , 24 Similarly, the results of the present experiment showed that RAD001 treatment of RCC cells resulted in the upregulation of LC3-II/I and downregulation of p62, which are typical features of autophagy induction, suggesting that autophagy by 786-O and A498 cells was induced by RAD001 treatment. So, high concentrations of RAD001 were used in this experiment due to the grade of the RCC cell lines 786-O and A498.…”

Section: Discussionsupporting

confidence: 74%

Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

Zeng¹,

Tian²,

Wang³

et al. 2018

DDDT

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AimThe mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway.Methods and results:RAD001 strongly induced autophagy of RCC cells in a dose- and time-dependent manner, as confirmed by Western blot analysis. Importantly, suppression of autophagy by the pharmacological inhibitor chloroquine effectively enhanced RAD001-induced apoptotic cytotoxicity, as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blot analysis, indicating a cytoprotective role for RAD001-induced autophagy. In addition, as was shown by the MTT assay, flow cytometry, and Western blot analysis, RAD001 robustly activated ERK, but not c-Jun N-terminal kinase and p38. Activation of ERK was inhibited by the pharmacological inhibitor selumetinib (AZD6244), which effectively promoted RAD001-induced cell death. Moreover, employing AZD6244 markedly attenuated RAD001-induced autophagy and enhanced RAD001-induced apoptosis, which play a central role in RAD001-induced cell death. Furthermore, RAD001-induced autophagy is regulated by ERK-mediated phosphorylation of Beclin-1 and B-cell lymphoma 2, as confirmed by Western blot analysis.ConclusionThese results suggest that RAD001-induced autophagy involves activation of the ERK, which may impair cytotoxicity of RAD001 in RCC cells. Thus, inhibition of the activation of ERK pathway-mediated autophagy may be useful to overcome chemoresistance to RAD001.

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Section: Discussionsupporting

confidence: 74%

Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

Zeng¹,

Tian²,

Wang³

et al. 2018

DDDT

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“…Recent studies have shown that multiple anticancer treatments result in the disorders of excessive autophagy and further lead to cancer cell death [14,15]. The Akt/mTOR pathway is suggested to play a key role in nutrient‐induced autophagy and is tightly correlated with oncogenesis in different cancer cells [16]. However, whether MA could induce autophagic death through this pathway in thyroid cancer cells has never been explored.…”

Section: Introductionmentioning

confidence: 99%

Mulberry anthocyanins improves thyroid cancer progression mainly by inducing apoptosis and autophagy cell death

Long

Zhang

Wang

et al. 2017

The Kaohsiung J of Med Scie

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Dietary anthocyanin compounds have multiple biological effects, including antioxidant, anti-inflammatory, and anti-atherosclerotic characteristics. The present study evaluated the anti-tumor capacity of mulberry anthocyanins (MA) in thyroid cancer cells. Our data showed that MA suppressed SW1736 and HTh-7 cell proliferation in a time- and dose-dependent manner. Meanwhile, flow cytometry results indicated that MA significantly increased SW1736 and HTh-7 cell apoptosis. We additionally observed that SW1736 and HTh-7 cell autophagy was markedly enhanced after MA treatment. Importantly, anthocyanin-induced cell death was largely abolished by 3-methyladenine (3-MA) or chloroquine diphosphate salt (CQ) treatment, suggesting that MA-induced SW1736 and HTh-7 cell death was partially dependent on autophagy. In addition, activation of protein kinase B (Akt), mammalian target of rapamycin (mTOR), and ribosomal protein S6 (S6) were significantly suppressed by anthocyanin exposure. In summary, MA may serve as an adjunctive therapy for thyroid cancer patients through induction of apoptosis and autophagy-dependent cell death.

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“…Among recent reports on the antitumor potential of glycyrrhizin (8), its cytotoxicity toward HepG2 and MHCC97-H hepatocellular carcinoma cells was found to be mediated by autophagy induced from the inhibition of Aκt/mTOR signaling [47]. It is worth mentioning that Glycyrrhiza uralensis Fisch.…”

Section: Lupane-type Triterpenoidsmentioning

confidence: 99%

Natural Product Triterpenoids and Their Semi-Synthetic Derivatives with Potential Anticancer Activity

Ren

Kinghorn

2019

Planta Med

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Triterpenoids are distributed widely in higher plants and are of interest because of their structural diversity and broad range of bioactivities. In particular, there is a very large literature on the propensity of a variety of triterpenoids to act as potential anticancer agents. In the present review, the anticancer potential is summarized for naturally occurring triterpenoids and their semi-synthetic derivatives, including examples of lupane-, oleanane-, ursane-, and cucurbitane-type pentacyclic triterpenoids, along with dammarane-type tetracyclic triterpenes including ginsenosides and their sapogenins and dichapetalins, which have been characterized as antitumor leads from higher plants. Preliminary structure-activity relationships and reported mechanisms of the antineoplastic-related activity are included. Prior studies for triterpenoids of plant origin are supportive of additional work being conducted on the more detailed biological and mechanistic evaluation for the progression of this type of natural products as possible cancer chemotherapeutic agents.

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The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma

Cited by 33 publications

References 41 publications

Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

Mulberry anthocyanins improves thyroid cancer progression mainly by inducing apoptosis and autophagy cell death

Natural Product Triterpenoids and Their Semi-Synthetic Derivatives with Potential Anticancer Activity

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