FAK-ERK activation in cell/matrix adhesion induced by the loss of apolipoprotein E stimulates the malignant progression of ovarian cancer

Lai, Hui‐Ling; Zhao, Xuejiao; Yu, Qin; Ding, Yi; Chen, Ruqi; Li, Guannan; Labrie, Marilyne; Ding, Zhiyong; Zhou, Jianfeng; Hu, Junbo; Ma, Ding; Fang, Yong; Gao, Qinglei

doi:10.1186/s13046-018-0696-4

Cited by 22 publications

(16 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mechanistically, we have provided evidence that the activation of FAK/MEK-1/ERK1/2 signaling, which in turn induces MMP-9 expression, is involved in HK2-mediated regulation of cell migration and invasion. This pathway is linked to the formation and turnover of focal adhesions, which is vital for tumor cell invasion and metastasis [18], including in ovarian [29,30] and gastric [31] cancers. Moreover, uPA and VEGF expression have both been shown to be associated with tumor stage, metastasis and patient survival in ovarian cancer [32,33].…”

Section: Discussionmentioning

confidence: 99%

Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades

Siu

Jiang

Wang

et al. 2019

Cancers

View full text Add to dashboard Cite

Metabolic reprogramming is a common phenomenon in cancers. Thus, glycolytic enzymes could be exploited to selectively target cancer cells in cancer therapy. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in glucose metabolism. Here, we demonstrated that HK2 was overexpressed in ovarian cancer and displayed significantly higher expression in ascites and metastatic foci. HK2 expression was significantly associated with advanced stage and high-grade cancers, and was an independent prognostic factor. Functionally, knockdown of HK2 in ovarian cancer cell lines and ascites-derived tumor cells hindered lactate production, cell migration and invasion, and cell stemness properties, along with reduced FAK/ERK1/2 activation and metastasis- and stemness-related genes. 2-DG, a glycolysis inhibitor, retarded cell migration and invasion and reduced stemness properties. Inversely, overexpression of HK2 promoted cell migration and invasion through the FAK/ERK1/2/MMP9 pathway, and enhanced stemness properties via the FAK/ERK1/2/NANOG/SOX9 cascade. HK2 abrogation impeded in vivo tumor growth and dissemination. Notably, ovarian cancer-associated fibroblast-derived IL-6 contributed to its up-regulation. In conclusion, HK2, which is regulated by the tumor microenvironment, controls lactate production and contributes to ovarian cancer metastasis and stemness regulation via FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression. HK2 could be a potential prognostic marker and therapeutic target for ovarian cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades

Siu

Jiang

Wang

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…The multifaceted interactions of FAK with various signal transduction mediators may contribute to the FAK-dependent processes involved in cancer development [19]. Indeed, FAK action has been associated to aggressive cancer features as the cell adhesion and spreading [20–22], the enhancement of cell proliferation and survival [23, 24] and the facilitation of invasive cell phenotypes [25–27]. In this context, it is worth mentioning that FAK was shown to be over-expressed in a wide variety of human malignancies, including invasive and metastatic breast tumors [28–30].…”

Section: Introductionmentioning

confidence: 99%

Focal adhesion kinase (FAK) activation by estrogens involves GPER in triple-negative breast cancer cells

Rigiracciolo

Santolla

Lappano

et al. 2019

J Exp Clin Cancer Res

View full text Add to dashboard Cite

BackgroundFocal adhesion kinase (FAK) is a cytoplasmatic protein tyrosine kinase that associates with both integrins and growth factor receptors toward the adhesion, migration and invasion of cancer cells. The G-protein coupled estrogen receptor (GPER) has been involved in the stimulatory action of estrogens in breast tumor. In this study, we have investigated the engagement of FAK by GPER signaling in triple negative breast cancer (TNBC) cells.MethodsPublicly available large-scale database and patient data sets derived from “The Cancer Genome Atlas” (TCGA; www.cbioportal.org) were used to assess FAK expression in TNBC, non-TNBC tumors and normal breast tissues. MDA-MB 231 and SUM159 TNBC cells were used as model system. The levels of phosphorylated FAK, other transduction mediators and target genes were detected by western blotting analysis. Focal adhesion assay was carried out in order to determine the focal adhesion points and the formation of focal adhesions (FAs). Luciferase assays were performed to evaluate the promoters activity of c-FOS, EGR1 and CTGF upon GPER activation. The mRNA expression of the aforementioned genes was measured by real time-PCR. Boyden chamber and wound healing assays were used in order to evaluate cell migration. The statistical analysis was performed by ANOVA.ResultsWe first determined by bioinformatic analysis that the mRNA expression levels of the gene encoding FAK, namely PTK2, is higher in TNBC respect to non-TNBC and normal breast tissues. Next, we found that estrogenic GPER signaling triggers Y397 FAK phosphorylation as well as the increase of focal adhesion points (FAs) in TNBC cells. Besides, we ascertained that GPER and FAK activation are involved in the STAT3 nuclear accumulation and gene expression changes. As biological counterpart, we show that FAK inhibition prevents the migration of TNBC cells upon GPER activation.ConclusionsThe present data provide novel insights regarding the action of FAK in TNBC. Moreover, on the basis of our findings estrogenic GPER signaling may be considered among the transduction mechanisms engaging FAK toward breast cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1056-8) contains supplementary material, which is available to authorized users.

show abstract

“…Thus, knockdown of G0S2 may cause downregulation of Src and FAK activity through suppression of integrin α5 and β1 expression. Furthermore, ERK1/2 is also activated by induction of integrin α5β1 expression (Danen and Yamada, 2001) and induce cell-matrix adhesion (Kim and Gumbiner, 2015; Lai et al ., 2018). Since p130 Crk-associated substrate (CAS) phosphorylation by integrin α5β1 enhances adhesion-mediated cell survival and migration by interaction with focal adhesion proteins, paxillin, and tensin (Huveneers and Danen, 2009), it may be possible that G0S2 activates CAS phosphorylation to promote cell motility and metastasis.…”

Section: Discussionmentioning

confidence: 99%

G0/G1 Switch 2 Induces Cell Survival and Metastasis through Integrin-Mediated Signal Transduction in Human Invasive Breast Cancer Cells

Cho

Kwon

et al. 2019

Biomolecules & Therapeutics

View full text Add to dashboard Cite

Human breast cancer cell line, MDA-MB-231, is highly invasive and aggressive, compared to less invasive cell line, MCF-7. To explore the genes that might influence the malignancy of MDA-MB-231, DNA microarray analysis was performed. The results showed that G0/G1 switch 2 (G0S2) was one of the most highly expressed genes among the genes upregulated in MDA-MB-231. Although G0S2 acts as a direct inhibitor of adipose triglyceride lipase, action of G0S2 in cancer progression is not yet understood. To investigate whether G0S2 affects invasiveness of MDA-MB-231 cells, G0S2 expression was inhibited using siRNA, which led to decreased cell proliferation, migration, and invasion of MDA-MB-231 cells. Consequently, G0S2 inhibition inactivated integrin-regulated FAK-Src signaling, which promoted Hippo signaling and inactivated ERK1/2 signaling. In addition, G0S2 downregulation decreased β-catenin expression, while E-cadherin expression was increased. It was demonstrated for the first time that G0S2 mediates the Hippo pathway and induces epithelial to mesenchymal transition (EMT). Taken together, our results suggest that G0S2 is a major factor contributing to cell survival and metastasis of MDA-MB-231 cells.

show abstract

FAK-ERK activation in cell/matrix adhesion induced by the loss of apolipoprotein E stimulates the malignant progression of ovarian cancer

Cited by 22 publications

References 51 publications

Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades

Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades

Focal adhesion kinase (FAK) activation by estrogens involves GPER in triple-negative breast cancer cells

G0/G1 Switch 2 Induces Cell Survival and Metastasis through Integrin-Mediated Signal Transduction in Human Invasive Breast Cancer Cells

Contact Info

Product

Resources

About