The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells

Yin, Junqiang; Wen, Li-Li; Wu, Li; Gao, Zhenhua; Huang, Gang; Wang, Jin; Zou, Changye; Tan, Pingxian; Yong, Bicheng; Jia, Qiang; Shen, Jingnan

doi:10.1016/j.toxlet.2012.11.006

Cited by 36 publications

(33 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lung and oral cancers display high levels of inactive pGSK-3β (ser9) [55]. Alternatively, our findings contradict a recent report that cinobufagin, a cardenolide, inactivates GSK-3β via serine 9 phosphorylation leading to decreased p65 NF-kB expression and apoptosis in osteosarcoma cells [56]. Cardiac glycosides and cardenolides are known to target (1) over-expressed NF-kB in cancer cells [13,14,24] and (2) upstream Bim, Bak and Bax that target Mcl-1 [21,24].…”

Section: Discussioncontrasting

confidence: 73%

Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation

Pongrakhananon¹,

Stueckle²,

Wang³

et al. 2014

Biochemical Pharmacology

View full text Add to dashboard Cite

Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50 = 11.9 nM) than digitoxin (IC50 = 90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.

show abstract

Section: Discussioncontrasting

confidence: 73%

Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation

Pongrakhananon¹,

Stueckle²,

Wang³

et al. 2014

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…Owing to their safety, long-term use, and their ability to target multiple pathways, there is a renewed interest in understanding the molecular mechanisms underlying their activity. Our previous studies have also provided evidence of some natural agents having potential anti-osteosarcoma activity, such as dihydromyricetin, cinobufagin, and bufalin (19,39,40). However, there is no evidence at the cellular level or in animal models for such an effect of DGT on osteosarcoma progression.…”

Section: Discussionmentioning

confidence: 99%

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Zhao

Jia

et al. 2018

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma.Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro. The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array.Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3b. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3b inactivation.Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3b inactivation-mediated repression of the Hedgehog/Gli1 pathway.

show abstract

“…The two tumor-derived osteoblast cell lines used in this study, MG-63 and Saos-2, are well characterized and exhibit similar, though not identical, phenotypes to normal human osteoblasts (Pautke et al, 2004; Czekanska et al, 2012). MG-63 and Saos-2 cell lines are routinely used to study apoptosis and utilize many of the pathways known to exist in normal osteoblasts such as caspases, MAPKs, GSK-3β/NF-κB, Wnt/β-catenin pathways, and BcL-2 family members (Arbon et al, 2012; Yin et al, 2013; Shangguan et al, 2014; Hun et al, 2015; Papa et al, 2015; Wang et al, 2015). Hence for mechanistic studies, these cell lines are a suitable model to study apoptosis pathways that also exist in osteoblasts in vivo (Bellido and Plotkin, 2011).…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic roles of Ca+2/calmodulin-dependent pathways in regulating cadmium-induced toxicity in human osteoblast-like cell lines

Burwell

Goodwin

et al. 2016

Toxicology Letters

View full text Add to dashboard Cite

The heavy metal cadmium is a widespread environmental contaminant that has gained public attention due to the global increase in cadmium-containing electronic waste. Human exposure to cadmium is linked to the pathogenesis of osteoporosis. We previously reported cadmium induces apoptosis and decreases alkaline phosphatase mRNA expression via extracellular signal-regulated protein kinase (ERK) activation in Saos-2 bone-forming osteoblasts. This study examines the mechanisms of cadmium-induced osteotoxicity by investigating roles of Ca+2/calmodulin-dependent protein kinase (CAMK) pathways. Saos-2 or MG-63 cells were treated for 24 or 48 h with 5 μM CdCl2 alone or in combination with calmodulin-dependent phosphodiesterase (PDE) inhibitor CGS-9343β; calmodulin-dependent kinase kinase (CAMKK) inhibitor STO-609; or calmodulin-dependent kinase II (CAMKII) inhibitor KN-93. CGS-9343β protected against cadmium-induced toxicity and attenuated ERK activation; STO-609 enhanced toxicity and exacerbated ERK activation, whereas KN-93 had no detectable effect on cadmium-induced toxicity. Furthermore, CGS-9343β co-treatment attenuated cadmium-induced apoptosis; but CGS-9343β did not recover cadmium-induced decrease in ALP activity. The major findings suggest the calmodulin-dependent PDE pathway facilitates cadmium-induced ERK activation leading to apoptosis, whereas the CAMKK pathway plays a protective role against cadmium-induced osteotoxicity via ERK signaling. This research distinguishes itself by identifying pleiotropic roles for CAMK pathways in mediating cadmium’s toxicity in osteoblasts.

show abstract

The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells

Cited by 36 publications

References 30 publications

Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation

Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Pleiotropic roles of Ca+2/calmodulin-dependent pathways in regulating cadmium-induced toxicity in human osteoblast-like cell lines

Contact Info

Product

Resources

About