Methylisoindigo preferentially kills cancer stem cells by interfering cell metabolism via inhibition of LKB1 and activation of AMPK in PDACs

Cheng, Xinlai; Kim, Jee Young; Ghafoory, Shahrouz; Duvaci, Tijen; Rafiee, Roya; Theobald, Jannick; Alborzinia, Hamed; Holenya, Pavlo; Fredebohm, Johannes; Merz, Karl Heinz; Mehrabi, Arianeb; Hafezi, Mohammadreza; Saffari, Arash; Eisenbrand, Gerhard; Hoheisel, Jörg D.; Wölfl, Stefan

doi:10.1016/j.molonc.2016.01.008

Cited by 42 publications

(48 citation statements)

References 75 publications

(147 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies found that meisoindigo can preferentially kill cancer stem cells by interfering cell metabolism via inhibition of LKB1 and activation of AMPK in PanC . Similar results have also been drawn from metformin, which influences PanC progression by activating the LKB1‐AMPK pathway, including inhibition of cell division, promotion of apoptosis, and autophagy, downregulation of circulating insulin, and activation of the immune system …”

Section: Introductionsupporting

confidence: 57%

Genetic variants in the liver kinase B1‐AMP‐activated protein kinase pathway genes and pancreatic cancer risk

Qian

Liu

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

The liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway has been identified as a new target for cancer therapy, because it controls the glucose and lipid metabolism in response to alterations in nutrients and intracellular energy levels. In the present study, we aimed to identify genetic variants of the LKB1-AMPK pathway genes and their associations with pancreatic cancer (PanC) risk using 15 418 participants of European ancestry from two previously published PanC genome-wide association studies. We found that six novel tagging single-nucleotide polymorphisms (SNPs) (i.e, MAP2 rs35075084 T > deletion, PRKAG2 rs2727572 C > T and rs34852782 A > deletion, TP53 rs9895829 A > G, and RPTOR rs62068300 G > A and rs3751936 G > C) were significantly associated with an increased PanC risk. The multivariate logistic regression model incorporating the number of unfavorable genotypes (NUGs) with adjustment for age and sex showed that carriers with five to six NUGs had an increased PanC risk (odds ratio = 1.24, 95% confidence interval = 1.16-1.32 and P < 0.0001), compared to those with zero to four NUGs. Subsequent expression quantitative trait loci (eQTL) analysis further revealed that these SNPs were associated with significantly altered mRNA expression levels either in 373 normal lymphoblastoid cell lines (TP53 SNP rs9895829, P < 0.05) or in whole blood cells of 369 normal donors from the genotype-tissue expression project (GTEx) database [RPTOR SNP rs60268947 and rs28434589, both in high linkage disequilibrium (r 2 > 0.9) with RPTOR rs62068300, P < 0.001]. Collectively, our findings suggest that these novel SNPs in the LKB1-AMPK pathway genes may modify susceptibility to PanC, possibly by influencing gene expression. K E Y W O R D S genome-wide association study, pancreatic cancer risk, single-nucleotide polymorphism (SNP) 1 | INTRODUCTION Pancreatic cancer (PanC) is one of the most lethal human malignancies, with an overall 5-year survival rate lower than 10% and a median survival of 6 months, and PanC is also the fourth leading cause of cancer-related death and is expected to become the second within the next decade in the United States. 1,2 The exact cause of PanC is not yet well understood, though several risk Molecular Carcinogenesis. 2019;58:1338-1348. wileyonlinelibrary.com/journal/mc 1338 |

show abstract

Section: Introductionsupporting

confidence: 57%

Genetic variants in the liver kinase B1‐AMP‐activated protein kinase pathway genes and pancreatic cancer risk

Qian

Liu

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…We first studied bortezomib-induced cell death in an apoptotic assay using annexin v/PI staining 29, 30 and confirmed that apoptosis occurred in both cell lines within 24 hrs of treatment (Fig. 1D).…”

Section: Resultsmentioning

confidence: 63%

“…The blots were detected with ECL solution as previously reported 29, 30 . 40 µg of total protein was resolved on 10% SDS-PAGE gels and immunoblotted with specific antibodies.…”

Section: Methodsmentioning

confidence: 99%

The essential role of TAp73 in bortezomib-induced apoptosis in p53-deficient colorectal cancer cells

Dabiri

Kálmán

Gürth

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Mutations in the tumor suppressor p53 are among the most highly occurring events in colorectal cancer (CRC). Such mutations have been shown to influence the sensitivity of cancer cells to chemotherapeutic agents. However their impact on the efficacy of the proteasomal inhibitor bortezomib remains controversial. We thus re-evaluated the toxicity of bortezomib in the CRC cell lines HCT116 wt (wild-type) and its p53−/− clone. Transient resistance to bortezomib treatment was observed in p53-null cells that was later accompanied by an increase in levels and nuclear translocation of TAp73, an isoform of the p53-homologue p73, as well as induction of apoptosis. Knockdown of p73 in p53−/− cells using CRISPR/Cas9 significantly prolonged the duration of resistance. Moreover, similar results were observed in HT-29 cells carrying mutated p53, but not human fibroblasts with expression of functional p53. Thus, our results clearly demonstrated that TAp73 served as a substitute for p53 in bortezomib-induced apoptosis in p53-deficient or mutated cells, implicating that TAp73 could be a potential therapeutic target for treatment of CRCs, in particular those lacking functional p53.

show abstract

“…Meisoindigo is significantly more resistant to protein kinases and exhibits higher antitumor activity than indirubin. Meisoindigo has numerous biological effects, including anti-neoplastic (Cheng et al, 2016), anti-inflammatory (Zhang et al, 2013) and antileukocyte chemotactic effects (Ye et al, 2017). However, whether meisoindigo exerts a neuroprotective action in ischemic stroke remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Meisoindigo Protects Against Focal Cerebral Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Regulating Microglia/Macrophage Polarization via TLR4/NF-κB Signaling Pathway

Jin

Zhou

et al. 2019

Front. Cell. Neurosci.

200

119

View full text Add to dashboard Cite

Ischemic stroke is a devastating disease with long-term disability. However, the pathogenesis is unclear and treatments are limited. Meisoindigo, a second-generation derivative of indirubin, has general water solubility and is well-tolerated. Previous studies have shown that meisoindigo reduces inflammation by inhibiting leukocyte chemotaxis and migration. In the present study, we investigated the hypothesis that meisoindigo was also protective against ischemic stroke, then evaluated its underlying mechanisms. In vivo, adult male C57BL/6J wild-type mice were used to produce a middle cerebral artery occlusion (MCAO) stroke model. On day three after reperfusion, obvious improvement in neurological scores, infarct volume reduction and cerebral edema amelioration were observed in meisoindigo treatment. Moreover, immunofluorescence staining and western-blot showed that the expression of NLRP3 inflammasome and its associated proteins in neurons and microglia was inhibited by meisoindigo. The effects of Meisoindigo on NLRP3 inflammasome inactivation and increased the M2 phenotype of microglia/macrophage through shifting from a M1 phenotype, which was possibly mediated by inhibition of TLR4/NF-κB. Furthermore, we verified the inhibitory effect of meisoindigo on TLR4/NF-κB signaling pathway, and found that meisoindigo treatment could significantly suppressed the expression of TLR4/NF-κB pathway-associated proteins in a dose-dependent manner, meanwhile, which resulted in downregulation of HMGB1 and IL-1β. Next, we established an in vitro oxygen glucose deprivation/Reperfusion (OGD/R) model in HT-22 and BV2 cells to simulate ischemic conditions. Cytotoxicity assay showed that meisoindigo substantially improved relative cell vitality and in HT-22 and BV2 cells following OGD/R in vitro. After suffering OGD/R, the TLR4/NF-κB pathway was activated, the expression of NLRP3 inflammasome-associated proteins and M1 microglia/macrophage were increased, but

show abstract

Methylisoindigo preferentially kills cancer stem cells by interfering cell metabolism via inhibition of LKB1 and activation of AMPK in PDACs

Abstract: 0 AMP-activated protein kinase; CHK2, check point kinase 2; DM, Dorsomorphin; ESA, epithelial cell adhesion molecule; GSH, glutathione; HSP27, heat shock protein 2; LKB1, liver kinase B1;

Cited by 42 publications

References 75 publications

Genetic variants in the liver kinase B1‐AMP‐activated protein kinase pathway genes and pancreatic cancer risk

Genetic variants in the liver kinase B1‐AMP‐activated protein kinase pathway genes and pancreatic cancer risk

The essential role of TAp73 in bortezomib-induced apoptosis in p53-deficient colorectal cancer cells

Meisoindigo Protects Against Focal Cerebral Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Regulating Microglia/Macrophage Polarization via TLR4/NF-κB Signaling Pathway

Contact Info

Product

Resources

About