FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis

Wang, Jiao; Liu, Shu; Yin, Yancun; Li, Mingjin; Wang, Bo; Yang, Li; Jiang, Yangfu

doi:10.1007/s10495-014-1071-3

Cited by 43 publications

(29 citation statements)

References 37 publications

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“…Phosphorylated FOXO exits the nucleus for degradation. Moreover, mTORC2 inhibition increased the expression level of FOXO1/3, and knockdown of FOXO3 abrogated rhein-induced apoptosis (25). Thus, we considered that the suppression of sorafenib-dependent AKT Ser473 phosphorylation by mTORC2 disassembly induced apoptosis via increased FOXO1.…”

Section: Discussionmentioning

confidence: 99%

Survival pathway of cholangiocarcinoma via AKT/mTOR signaling to escape RAF/MEK/ERK pathway inhibition by sorafenib

et al. 2017

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Cholangiocarcinoma (CCC) is a strongly aggressive malignancy for which surgical resection is the only potential curative therapy. Sorafenib, a multikinase inhibitor of the RAF/MEK/ERK pathway, is a molecular-targeted drug that is approved for hepatocellular carcinoma (HCC) but not for CCC. The differences in signaling pathway characteristics under sorafenib treatment between HCC (HLF, Huh7, PLC/PRF/5) and CCC (RBE, YSCCC, Huh28) cell lines were therefore investigated using cell proliferation, western blotting, and apoptosis analyses. Sorafenib inhibited cell growth significantly less in CCC cells than in HCC cells, with lower suppression of ERK phosphorylation. Significantly decreased AKT Ser473 phosphorylation in HCC cells, and conversely enhanced phosphorylation of AKT Ser473 and mTORC2 in CCC cells, were observed with sorafenib treatment. Disassembly of the mTORC2 complex in RBE cells with siRNA targeting Rictor resulted in the downregulation of AKT Ser473 phosphorylation and enhanced apoptosis presumably via increased FOXO1, which consequently suppressed RBE cell proliferation. Phosphorylation of mTORC1 and autophagy were not influenced by sorafenib in CCC cells. Simultaneous administration of everolimus to suppress activated mTORC1 in RBE cells revealed that combined everolimus and sorafenib treatment under mTORC2 disassembly could enhance growth inhibition through the suppression of both sorafenib- and everolimus-dependent AKT Ser473 phosphorylation in addition to the inhibition of mTORC1 phosphorylation. Prevention of escape by AKT/mTOR signaling from the RAF/MEK/ERK pathway in sorafenib treatment by suppressing mTORC2 activity may lead to promising new approaches in CCC therapy.

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Section: Discussionmentioning

confidence: 99%

Survival pathway of cholangiocarcinoma via AKT/mTOR signaling to escape RAF/MEK/ERK pathway inhibition by sorafenib

et al. 2017

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“…Rhein mainly regulates the two key proteins, namely, PI3K and AKT, to influence this signaling pathway. The majority of researchers agreed that rhein can inhibit the activation of PI3K and p-AKT, but it does not have an inhibitory effect on the total AKT (Fernand et al, 2011 ; Cong et al, 2012a ; Tsang and Bian, 2015 ; Wang et al, 2015 ). However, rhein treatment to hepatocytes results in the increase of p-AKT1 or PKC (Panigrahi et al, 2015 ).…”

Section: Rhein Regulation On Signal Transductionmentioning

confidence: 99%

A Comprehensive and System Review for the Pharmacological Mechanism of Action of Rhein, an Active Anthraquinone Ingredient

et al. 2016

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Rhein is a major medicinal ingredient isolated from several traditional Chinese medicines, including Rheum palmatum L., Aloe barbadensis Miller, Cassia angustifolia Vahl., and Polygonum multiflorum Thunb. Rhein has various pharmacological activities, such as anti-inflammatory, antitumor, antioxidant, antifibrosis, hepatoprotective, and nephroprotective activities. Although more than 100 articles in PubMed are involved in the pharmacological mechanism of action of rhein, only a few focus on the relationship of crosstalk among multiple pharmacological mechanisms. The mechanism of rhein involves multiple pathways which contain close interactions. From the overall perspective, the pathways which are related to the targets of rhein, are initiated by the membrane receptor. Then, MAPK and PI3K-AKT parallel signaling pathways are activated, and several downstream pathways are affected, thereby eventually regulating cell cycle and apoptosis. The therapeutic effect of rhein, as a multitarget molecule, is the synergistic and comprehensive result of the involvement of multiple pathways rather than the blocking or activation of a single signaling pathway. We review the pharmacological mechanisms of action of rhein by consulting literature published in the last 100 years in PubMed. We then summarize these pharmacological mechanisms from a comprehensive, interactive, and crosstalk perspective. In general, the molecular mechanism of action of drug must be understood from a systematic and holistic perspective, which can provide a theoretical basis for precise treatment and rational drug use.

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“…Antrodia camphorate extracts have been demonstrated that activation of caspase-3, -8, and -9 and the increase in the cytosolic level of cytochrome c were accompanied by increasing the expression levels of Bak, Bad and Bim in HeLa and C-33A cells [36]. Rhein also increased the expression of Bim and FOXO3a in MCF-7 and HepG2 cells during apoptosis [37]. Our group also has demonstrated that an analogue of curcumin, dibenzylideneacetone enhanced Bax expression resulting in apoptosis in oral cancer cells [38].…”

Section: Discussionmentioning

confidence: 98%

Chemotherapeutic Effect of Withaferin A in Human Oral Cancer Cells

Yang¹,

Kim²,

Shin³

et al. 2015

JCT

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Withaferin A (WA) is a bioactive compound derived from a medicinal plant Withania somnifera and has potential therapeutic effects against various types of cancers. The purpose of this study is to investigate an apoptotic effect of WA and identify its molecular target in HSC-3 and HSC-4 human oral cancer cell lines using Trypan blue exclusion assay, DAPI staining and western blotting. WA inhibited cell viability and induced apoptosis in a concentration-or time-dependent manner, as evidenced by induction of nuclear condensation and fragmentation, activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) cleavage. WA-induced apoptosis was partly diminished by Z-VAD, a pancaspase inhibitor. WA also increased Bim and Bax protein in HSC-3 and HSC-4 cells, respectively. These results suggest that WA may be a potential chemotherapeutic drug candidate against human oral cancer.

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FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis

Cited by 43 publications

References 37 publications

Survival pathway of cholangiocarcinoma via AKT/mTOR signaling to escape RAF/MEK/ERK pathway inhibition by sorafenib

Survival pathway of cholangiocarcinoma via AKT/mTOR signaling to escape RAF/MEK/ERK pathway inhibition by sorafenib

A Comprehensive and System Review for the Pharmacological Mechanism of Action of Rhein, an Active Anthraquinone Ingredient

Chemotherapeutic Effect of Withaferin A in Human Oral Cancer Cells

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