Tautomycetin Induces Apoptosis by Inactivating Akt Through a PP1-Independent Signaling Pathway in Human Breast Cancer Cells

Niu, Mingshan; Sun, Yan; Liu, Xuejiao; Tang, Li; Qiu, Rong-Guo

doi:10.1254/jphs.12206fp

Cited by 11 publications

(8 citation statements)

References 25 publications

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“…It inactivated serine-threonine kinase Akt (also called as protein kinase B), which is reported to be required for NF-κB activation by TNF, 30) through a PP1-independent pathway. 31) Thus, tautomycetin might also suppress the activation of NF-κB independently of PP1 inhibition. Based on these previous reports, guanabenz and tautomycetin might have pleiotropic potential for NF-κB suppression.…”

Section: Discussionmentioning

confidence: 99%

eIF2α-Independent Inhibition of TNF-α-Triggered NF-κB Activation by Salubrinal

Nakajima

Chi

Gao

et al. 2015

Biological & Pharmaceutical Bulletin

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Salubrinal is a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2α (eIF2α). In previous reports, salubrinal was shown to have the potential to inhibit the activation of nuclear factor-κB (NF-κB) by several stimuli. However, the effects of salubrinal on NF-κB signaling are largely unknown. In this study, we investigated whether and how salubrinal affects NF-κB activation induced by tumor necrosis factor (TNF)-α and interleukin (IL)-1β. We found that salubrinal selectively blocked TNF-α-but not IL-1β-induced activation of NF-κB. This inhibitory effect occurred upstream of transforming growth factor (TGF)-β-activated kinase 1 (TAK1). Further experiments revealed that salubrinal blocked TNF-α-triggered NF-κB activation independent of its action on eIF2α because knockdown of eIF2α by small interfering RNA (siRNA) did not reverse the inhibitory effect of salubrinal on NF-κB. Moreover, guanabenz, a selective inhibitor of the regulatory subunit of protein phosphatase (PP) 1, also preferentially inhibited TNF-α-triggered activation of NF-κB. These findings raise the possibility that salubrinal may selectively block TNF-α-triggered activation of the NF-κB pathway through inhibition of the PP1 complex.Key words salubrinal; nuclear factor-κB; eukaryotic translation initiation factor 2α; protein phosphatase (PP) 1; guanabenz Salubrinal is a small molecule that inhibits the dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) through the suppression of protein phosphatase (PP) 1 catalytic subunits, resulting in sustained phosphorylation of eIF2α on Ser51. Through this effect, salubrinal protects cells from endoplasmic reticulum (ER) stress-mediated apoptosis.1) It has been shown that salubrinal influences several signaling pathways involved in apoptosis, autophagy and bone homeostasis.2-4) The nuclear factor-κB (NF-κB) pathway is also a target of salubrinal. Recently, Huang et al. reported that salubrinal protected against β-amyloid-triggered neuronal cell death and microglial activation through the suppression of NF-κB activation. 5) Moreover, Hamamura et al. suggested that salubrinal reduced the inflammatory cytokine-driven expression of matrix metalloproteinase 13 via blockade of the p38 mitogen-activated protein kinase pathway and the NF-κB pathway.6) Currently, however, the mechanism by which salubrinal regulates NF-κB remains largely unknown.The Rel/NF-κB family consists of five different members, namely, p50, p52, p65 (RelA), RelB and c-Rel, and functions as a transcription factor through the formation of homo-or heterodimers.7) NF-κB plays crucial roles in the regulation of inflammation, immune responses and apoptosis. 8) In unstimulated cells, NF-κB is retained in the cytoplasm through binding to inhibitors of NF-κB (IκBs). However, in response to several stimuli such as inflammatory cytokines, oxidative stress, ultraviolet light and bacterial components, IκB kinase (IKK) complex including IKKα, IKKβ and IKKγ (also called NF-κB essential modu...

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Section: Discussionmentioning

confidence: 99%

eIF2α-Independent Inhibition of TNF-α-Triggered NF-κB Activation by Salubrinal

Nakajima

Chi

Gao

et al. 2015

Biological & Pharmaceutical Bulletin

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“…The whole or nuclear cell extract of control and treated cells were used in Western blot analysis [20]. The protein extracts were resolved by SDS-PAGE.…”

Section: Methodsmentioning

confidence: 99%

Novel reversible selective inhibitor of CRM1 for targeted therapy in ovarian cancer

et al. 2015

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BackgroundOvarian cancer represents the most fatal type of gynecological malignancies. Unfortunately, there are still no effective targeted treatment strategies for ovarian cancer. Overexpression of CRM1 has been correlated with poor prognosis of patients with ovarian cancer.AimIn this study, we investigated the antitumor effects of a novel reversible inhibitor of CRM1 in ovarian cancer cells.MethodsThe effects of S109 on proliferation was detected by CCK-8, EdU, clonogenic assay. The protein expression were determined by Western blot. The subcellular localization of RanBP1 was analyzed by immunofluorescence microscopy assay.ResultsWe demonstrated that S109 could induce nuclear accumulation of RanBP1, a canonical biomarker for CRM1 inhibition. This effect was clearly reversible in the majority of the cells, whereas the inhibitory effect of LMB could not be reversed. Our data reveal that treatment with S109 results in decrease in proliferation and colonogenic capacity of ovarian cancer cells by arresting cell cycle. Mechanistically, S109 treatment increase the expression of the cyclin-dependent kinase inhibitor p21, while it reduced the expression of cell cycle promoting proteins, Cyclin D1 and Cyclin B. CRM1 level itself was also down-regulated following S109 treatment. Furthermore, the nuclei of cells incubated with S109 accumulated tumor suppressor proteins (Foxo1, p27 and IκB-α). More importantly, Cys528 mutation of CRM1 abolished the ability of S109 to block proliferation of ovarian cancer cells.ConclusionsTogether, our study identifies CRM1 as a valid target in ovarian cancer and provides a basis for the development of S109 in ovarian cancer.

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“…31 Approximately, 2 £ 10 4 HCT-15 cells in serum-free RPMI-1640 media with 0.1% DMSO and different concentrations of S109 (0.5 and 1 mM) were added to the top chamber, and the bottom chamber was filled with RPMI-1640 containing 10% FBS. After 36 hours of incubation, invading cells were fixed with 4% paraformaldehyde Figure 6.…”

Section: Invasion Assaymentioning

confidence: 99%

Novel reversible selective inhibitor of nuclear export shows that CRM1 is a target in colorectal cancer cells

Niu

Chong

Han

et al. 2015

Cancer Biology & Therapy

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Abbreviations: CRM1, chromosomal region maintenance 1; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; LMB, leptomycin B; NES, leucine-rich nuclear export signal; PI3K, phosphoinositide 3-kinase; RanBP1, Ran-binding protein 1.Colorectal cancer arises via a multistep carcinogenic process and the deregulation of multiple pathways. Thus, the simultaneous targeting of multiple pathways may be a promising therapeutic approach for colorectal treatment. CRM1 is an attractive cancer drug target, because it can regulate multiple pathways and tumor suppressor proteins. In this study, we investigated the anti-tumor activity of a novel reversible CRM1 inhibitor S109 in colorectal cancer. Our data demonstrate that S109 inhibits proliferation and induces cell cycle arrest in colorectal cancer cells. Mechanistically, we demonstrate that the activity of S109 is associated with the nuclear retention of major tumor suppress proteins. Furthermore, the Cys528 mutation of CRM1 prevented the ability of S109 to block nuclear export and inhibit the proliferation of colorectal cancer cells. Interestingly, S109 decreased the CRM1 protein level via proteasomal pathway. We argue that reversible CRM1 inhibitors but not irreversible inhibitors can induce the degradation of CRM1, because the dissociation of reversible inhibitors of CRM1 changes the conformation of CRM1. Taken together, these findings demonstrate that CRM1 is a valid target for the treatment of colorectal cancer and provide a basis for the development of S109 therapies for colorectal cancer.

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Tautomycetin Induces Apoptosis by Inactivating Akt Through a PP1-Independent Signaling Pathway in Human Breast Cancer Cells

Cited by 11 publications

References 25 publications

eIF2α-Independent Inhibition of TNF-α-Triggered NF-κB Activation by Salubrinal

eIF2α-Independent Inhibition of TNF-α-Triggered NF-κB Activation by Salubrinal

Novel reversible selective inhibitor of CRM1 for targeted therapy in ovarian cancer

Novel reversible selective inhibitor of nuclear export shows that CRM1 is a target in colorectal cancer cells

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