Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer

Park, Jae-Hyun; Rasch, Morten Grønbech; Qiu, Jing; Lund, Ida Katrine; Egeblad, Mikala

doi:10.1016/j.neo.2015.04.003

Cited by 28 publications

(24 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While our results implicated a positive feedback regulatory loop of AMPKα signaling, the possible involvement of other kinase signaling pathways, and up- or downstream mediators underlying this regulation, such as phosphorylation and regulation of IGF-1 receptor [47, 48], regulation of IGFs [49], forkhead box class O (FOXO) [50], and hypoxia-inducible factor (HIF) [51], among others, required to be elucidated in the future studies. In addition to inhibiting IGF effects [52], IGFBP1 also showed to suppress cancer cell proliferation, invasiveness and motility via stimulating or inhibiting several critical downstream genes and/or proteins [51, 53], which highlighted a tumor suppressor role of IGFBP1. Consistent with these, our results implied that the induction of IGFBP1 expression was required in stimulating the emodin-inhibited NSCLC growth.…”

Section: Discussionmentioning

confidence: 99%

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Tang¹,

Wu²,

Zheng³

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Emodin has anti-neoplastic activities on multiple tumors. However, the molecular mechanisms underlying this effect still remain to be fully understood. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays and flow cytometry, respectively. Cell invasion and migration were examined by transwell invasion and wound healing assays. Western blot analysis was performed to examine the phosphorylation and protein expression of AMP-activated protein kinase alpha (AMPKα), extracellular signaling-regulated kinase 1/2 (ERK1/2), peroxisome proliferators-activated receptor gamma (PPARγ), insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and the transcription factor Sp1. QRT-PCR was used to examine the mRNA levels of the IGFBP1 gene. Small interfering RNAs (siRNAs) were used to knockdown PPARγ and IGFBP1 genes. Exogenously expression of IGFBP1 and Sp1 was determined by transient transfection assays. IGFBP1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. In vivo nude mice xenograft model and bioluminescent imaging system were used to confirm the findings. Results: We showed that emodin induced cell cycle arrest of NSCLC cells. Emodin increased PPARγ protein and luciferase reporter activity, which were abolished by inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK)/ERK and AMPK. Silencing of PPARγ abrogated emodin-inhibited cell growth and cell cycle arrest. Furthermore, emodin elevated IGFBP1 mRNA, protein, and promoter activity through activation of PPARγ. Intriguingly, overexpressed Sp1 attenuated emodin-induced IGFBP1 expression, which was not observed in cells with silenced PPARγ gene. Moreover, silencing of IGFBP1 gene blunted emodin-induced inhibition of cell growth and cell cycle arrest. On the contrary, overexpressed IGFBP1 enhanced emodin-induced phosphorylation of AMPKα and ERK1/2, and restored emodin-inhibited growth in cells with silenced endogenous IGFBP1 gene. Emodin also inhibited growth of lung xenograft tumors and Sp1, and increased IGFBP1 and PPARγ protein expressions In vivo. Conclusion: Collectively, our results show that emodin inhibits growth of non-small-cell lung cancer (NSCLC) cells through ERK and AMPKα-mediated induction of PPARγ, followed by reduction of Sp1. This in turn induces IGFBP1 gene expression. Thus, the signaling cascades, positive feedback loop and cooperative interplay between transcription factors-induced the expression of IGFBP1 gene contribute to the overall responses of emodin. This study provides a novel mechanism by which emodin inhibits growth of human lung cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Tang¹,

Wu²,

Zheng³

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Tumors in this model have high numbers of infiltrating neutrophils and high expression of CXCL1 (22). Like 4T1 cells, C3(1)-Tag primary cancer cells induced NETs when co-cultured with mouse neutrophils (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, because we identified G-CSF as a critical factor in the induction of NETs by cancer cells, it is possible that cancer cell expression of G-CSF could identify patients at risk of developing NET-promoted metastasis. Both 4T1 cells and C3(1)-Tag tumors express high levels of G-CSF (22, 35), and they are both models of triple-negative breast cancer. Higher amounts of G-CSF are found in human patient samples of triple-negative breast cancers than of other subtypes (34).…”

Section: Discussionmentioning

confidence: 99%

Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps

et al. 2016

Self Cite

View full text Add to dashboard Cite

Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. Here, we show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with DNase I blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasis-promoting tumor-host interaction and a potential therapeutic target.

show abstract

“…Report showed that excess of IGFBP1 inhibited growth of breast cancer cells via inhibition of IGF receptor 1 binding to IGFs [29]. High expression of IGFBP mRNA was strongly correlated with better survival in breast cancer mouse model [30]. We previously observed that ursolic acid, a natural pentacyclic triterpenoid, and emodin, one anthraquinones constituents derivative isolated from the roots of rheum palmatuma, inhibited growth of hepatocellular carcinoma and lung cancer cells through induction of IGFBP1 gene expression, suggesting tumor suppressing role of this molecule [31, 32].…”

Section: Introductionmentioning

confidence: 99%

Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

Tang

Zheng

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Solamargine, one natural photochemical component from traditional plants, has been shown to have anti-cancers properties. We previously showed that solamargine inhibited the growth of non-small-cell lung cancer (NSCLC) cells through suppression of prostaglandin E2 (PGE₂) receptor EP4 gene and regulation of downstream signaling pathways. However, the detailed mechanism underlying this, especially in combination of metformin, a known AMPK activator, still remained to be determined. Methods: Cell viability was measured using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colorimetric 5-bromo-2-deoxyuridine (BrdU) ELISA methods, respectively. Western blot analysis and immunohistochemistry were performed to examine the phosphorylation and protein expressions of signal transducer and activator of transcription 3 (Stat3), SP1, forkhead box O3a (FOXO3a), and insulin-like growth factor (IGF)-IGF binding protein 1 (IGFBP1). The expression of IGFBP1 mRNA was measured by quantitative real time PCR (qRT-PCR). Silencing of FOXO3a and IGFBP1 were examined by siRNA procedures. Exogenously expression of SP1, FOXO3a, and IGFBP1 were carried out by transient transfection assays. The promoter activity of IGFBP1 was tested using Secrete-Pair^TM Dual Luminescence Assay Kit. A xenografted tumor model was used to further test the effect of solamargine in combining with metformin in vivo. Results: We further demonstrated that solamargine inhibited growth and induced cell cycle arrest in other NSCLC cell lines. Through mechanism-based approaches, we showed that solamargine decreased the phosphorylation of Stat3; In addition, solamargine induced FOXO3a, whereas reduced SP1 protein levels; all of which were abrogated in cells with overexpressed Stat3 gene. Interestingly, there is interaction between FOXO3a and SP1. Moreover, solamargine increased mRNA, protein expression and promoter activity of IGFBP1, which was not observed in cells with overexpressed SP1 or with silenced FOXO3a genes. Finally, ablation of IGFBP1 expression by siRNA blocked the effect of solamargine on cell growth inhibition. More importantly, there was a synergy of combination of solamargine and metformin. Similar findings were also observed in vivo. Conclusion: Our results show that solamargine increases IGFBP1 gene expression through inactivation of Stat3, followed by regulation and reciprocal interaction of FOXO3a and SP1 in vitro and in vivo. This ultimately leads to suppression of human lung cancer cell growth. Moreover, this is a synergy of solamargine in combination with metformin in this process. This study unravels a novel mechanism underlying the anti-lung cancer effects of solamargine in combination of metformin, and suggests a potential new lung cancer associated therapy.

show abstract

Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer

Cited by 28 publications

References 59 publications

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps

Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

Contact Info

Product

Resources

About