Aspafilioside B induces G2/M cell cycle arrest and apoptosis by up-regulating H-Ras and N-Ras via ERK and p38 MAPK signaling pathways in human hepatoma HepG2 cells

Liu, Wei; Ning, Rui; Chen, Ruini; Huang, Xuefeng; Dai, Qinsheng; Hu, Jinhua; Wang, Yuwen; Wu, Lili; Xiong, Jing; Hu, Gang; Guo, Qinglong; Yang, Jian; Wang, Hao

doi:10.1002/mc.22293

Cited by 42 publications

(16 citation statements)

References 48 publications

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“…Emodin may also induce apoptosis of colorectal cancer cells through activating p53/p38/Puma pathway by triggering ROS production (25). However, according to the study by Liu et al (26), aspafilioside B may induce G2 phase arrest and apoptosis by upregulate ERK and p38 phosphorylation, which is consistent with our result that the activation of ERK and p38 may induce apoptosis of HCC. We think the roles of the ERK and p38 are partly associated with cell type.…”

Section: Discussionsupporting

confidence: 91%

Emodin induces hepatocellular carcinoma cell apoptosis through MAPK and PI3K/AKT signaling pathways in vitro and in vivo

et al. 2016

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Abstract. Emodin is an active ingredient derived from root and rhizome of Rheum palmatum L and many studies have reported that it exhibits anticancer effects in a number of human tumors. However, there is little information demonstrating the possible effects of emodin on the proliferation and apoptosis of hepatocellular carcinoma (HCC). In the present study, we show that emodin may inhibit the proliferation of SMMC-7721 cells in a dose-and time-dependent manner and induced apoptosis of cells in a concentration-dependent manner after treatment for 24 h. Moreover, we further discovered that the possible molecular mechanisms involved may relate to the mitogenactivated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Emodin may induce the phosphorylation of extracellular-signal-regulated kinase (ERK) and p38 while mildly suppressed the expression of p-c-Jun-N-terminal kinase (p-JNK). However, emodin did not affect the expression of the total (t)-ERK, t-p38 or t-JNK. Furthermore, emodin also suppressed the activation of p-AKT, but not the t-AKT. In vivo, we found that emodin suppressed tumor growth in experimental mice without an obvious change in body weight, which may work through the antiproliferation and apoptosis inducing effects. Moreover, emodin improves the liver and kidney function in mice, revealing that emodin may improve the life quality of the mice with implanted tumors. In conclusion, the above findings indicate that emodin may be a potentially effective and safe drug to induce apoptosis of HCC.

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Section: Discussionsupporting

confidence: 91%

Emodin induces hepatocellular carcinoma cell apoptosis through MAPK and PI3K/AKT signaling pathways in vitro and in vivo

et al. 2016

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“…31 Some studies have reported that ERK-or JNK/MAPK activation induces G2/M phase arrest and apoptosis in solid tumors. [32][33][34][35][36] We found that palbociclib destabilizes HIF-1a and activates ERK1/2 under either normoxic or hypoxic conditions (Fig. 3).…”

Section: Discussionmentioning

confidence: 76%

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1a regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3b. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1a accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3b signaling and GSK-3b expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1a accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.

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“…Indeed, Aspafilioside B, a steroidal saponin extracted from Asparagus filicinus and a known active cytotoxic component, has been shown to induce apoptosis via ERK1/2 activation in HepG2 cells [38]. In addition, PD98059 completely blocked BBR-induced KLF6 and ATF3 expression in HepG2 and Hep3B cells, respectively suggesting that activation of the ERK1/2 pathway is involved in BBR’s-regulation of gene expression in the HCC cell line.…”

Section: Discussionmentioning

confidence: 99%

Berberine regulates the protein expression of multiple tumorigenesis-related genes in hepatocellular carcinoma cell lines

Chuang

Min

et al. 2017

Cancer Cell Int

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BackgroundHepatocellular carcinoma (HCC) is the seventh most common malignancy and the third leading cause of cancer-related death worldwide with an extremely grim prognosis. Berberine (BBR) has been found to inhibit proliferation of human HCC cells, although the underlying mechanism(s) are unclear.MethodsProtein expression was detected by Western blots. Cell viability was determined by using the CellTiter Assay kit.ResultsWe confirm that BBR treatment inhibits HepG2, Hep3B, and SNU-182 cell viability, and suggest that it regulates this proliferation via the modulation of multiple tumorigenesis-related genes protein expression. BBR treatment up-regulated protein expression of tumor suppressor genes, including Kruppel-like factor 6 (KLF6), activating transcription factor 3 (ATF3) and p21, while down-regulating the expression of selected oncogenes, including E2F transcription factor 1 (E2F1) and pituitary tumor transforming gene 1 (PTTG1). The specific extracellular signal–regulated kinases 1/2 (ERK1/2) inhibitor, PD98059, partially inhibited BBR effects including reduction of cell viability, and up-regulation of KLF6 and ATF3 expressions; although, PD98059 did not alter the down-regulation of E2F1 and PTTG1 expression by BBR.ConclusionsOur results suggest that BBR inhibits HCC cell viability by modulating multiple tumorigenesis-related genes, and that up-regulation of tumor suppressor genes by BBR is in part the result of ERK1/2 action. The results of this study augment our understanding of the mechanisms underlying the effect of BBR on hepatocellular cancers and provide further evidence as to the biological plausibility of this agent’s role in the treatment of these malignancies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-017-0429-3) contains supplementary material, which is available to authorized users.

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Aspafilioside B induces G2/M cell cycle arrest and apoptosis by up-regulating H-Ras and N-Ras via ERK and p38 MAPK signaling pathways in human hepatoma HepG2 cells

Cited by 42 publications

References 48 publications

Emodin induces hepatocellular carcinoma cell apoptosis through MAPK and PI3K/AKT signaling pathways in vitro and in vivo

Emodin induces hepatocellular carcinoma cell apoptosis through MAPK and PI3K/AKT signaling pathways in vitro and in vivo

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

Berberine regulates the protein expression of multiple tumorigenesis-related genes in hepatocellular carcinoma cell lines

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