Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of β-catenin, and enhanced tumor cell invasion

Lu, Zhimin; Ghosh, Sourav; Wang, Zhiyong; Hunter, Tony

doi:10.1016/s1535-6108(03)00304-0

Cited by 615 publications

(548 citation statements)

References 118 publications

Supporting

Mentioning

497

Contrasting

Unclassified

Order By: Relevance

“…Consistent with this observation, some of these repressors have been found expressed specifically at the invasive front of human invasive hepatocellular and breast carcinoma [15,16]. The expression of these repressors seems to be highly regulated by pathways, including canonical Wnt signaling, TGF-b (see below), FGF, EGF, Stat3 and nuclear factor k-B (NFk-B) signaling [17][18][19]). Notably, Snail1 is a highly unstable protein.…”

Section: Changes In Cell-cell and Cell-matrix Adhesionmentioning

confidence: 78%

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Kopfstein

Christofori

2006

Cell. Mol. Life Sci.

210

160

View full text Add to dashboard Cite

Abstract. The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix Cell. Mol. Life Sci. 63 (2006) 449-468 1420-682X/06/040449-20 DOI 10.1007/s00018-005-5296-8 © Birkhäuser Verlag, Basel, 2006 adhesion as well as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as initiation of the metastatic process.

show abstract

Section: Changes In Cell-cell and Cell-matrix Adhesionmentioning

confidence: 78%

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Kopfstein

Christofori

2006

Cell. Mol. Life Sci.

210

160

View full text Add to dashboard Cite

show abstract

“…Although considerable data support a role of receptor tyrosine kinases, including EGFR, in the induction of EMT (Thiery, 2002;Conacci-Sorrell et al, 2003;Lu et al, 2003;Cavallaro and Christofori, 2004;Lo et al, 2007), there remains little consensus about which downstream pathways are necessary to mediate EGFR-induced EMT. Studies within carcinoma cell lines from disparate epithelial tissues have supplied evidence for several different signaling pathways (b-catenin-TCF/LEF-1, ERK, STAT3), as well as alternate repressors of E-cadherin transcription (Twist, Slug) involved in activation of EMT (Conacci-Sorrell et al, 2003;Lu et al, 2003;Lo et al, 2007), reflective of the fact that cancer cells can use completely distinct pathways under diverse biological contexts.…”

Section: Discussionmentioning

confidence: 99%

“…Studies within carcinoma cell lines from disparate epithelial tissues have supplied evidence for several different signaling pathways (b-catenin-TCF/LEF-1, ERK, STAT3), as well as alternate repressors of E-cadherin transcription (Twist, Slug) involved in activation of EMT (Conacci-Sorrell et al, 2003;Lu et al, 2003;Lo et al, 2007), reflective of the fact that cancer cells can use completely distinct pathways under diverse biological contexts. Our work in prostate cancer cells, in addition to the study in cervical cancer cells (Lee et al, 2008), adds yet another mechanistic pathway by which carcinoma cells undergo EMT, specifically an EGF/EGFR-mediated EMT pathway through Akt inhibition of GSK3b, followed by stabilization of Snail and downregulation of E-cadherin (EGFR-Akt-GSK3b-Snail-E-cadherin-EMT).…”

Section: Discussionmentioning

confidence: 99%

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

et al. 2010

View full text Add to dashboard Cite

Upregulation of epidermal growth factor receptor (EGFR) and subsequent increases in extracellular-regulated kinase (ERK) and Akt signaling are implicated in prostate cancer progression. Impaired endocytic downregulation of EGFR also contributes to oncogenic phenotypes such as metastasis. Thus, understanding the roles of divergent signaling pathways in the regulation of EGFR trafficking and EGFRdriven invasive migration may enable the development of more effective therapies. In this study, we use the human prostate cancer cell lines, DU145 and PC3, to investigate the effects of both the ERK and Akt pathways on epidermal growth factor (EGF)-mediated EGFR signaling, trafficking and cell motility. We show that DU145 and PC3 cells overexpress EGFR and migrate in a ligand (EGF)-dependent manner. Next, we show that pharmacological inhibition of ERK (but not Akt) signaling enhances EGFinduced EGFR activation, ubiquitination and downregulation, and may lead to enhanced receptor turnover. These findings negatively correlate with ERK-mediated threonine phosphorylation of EGFR, implicating it as a possible mechanism. Further, we uncover that EGF promotes disassembly of cell-cell junctions, downregulation of E-cadherin and upregulation of the transcriptional repressor, Snail, typical characteristics of epithelial-mesenchymal transition (EMT). These effects are dependent on activation of Akt, as inhibition of Akt signaling abolishes EGF/EGFR-driven cell migration and EMT. Knockdown of endogenous Snail also prevents EGFR-mediated downregulation of E-cadherin, EMT and cell migration. Surprisingly, inhibition of the ERK pathway augments EGFR-dependent motility, occurring concomitantly with elevation of EGF-induced Akt activity. Collectively, our results suggest that EGF-triggered ERK activation has profound feedback on EGFR signaling and trafficking by EGFR threonine phosphorylation, and Akt has a pivotal role in EGFR-mediated cell migration by activating EMT. More important, our results also suggest that therapeutic targeting of ERK signaling may have undesirable outcomes (for example, augmenting EGFR-driven motility).

show abstract

“…Therefore, it is possible that suppression of AP-1 activity is also involved in the inhibition of proliferation by SASP. Several studies have shown that caveolin-1 functions as an important player in Wnt-independent regulation of transcriptional activity of b-catenin (Lu et al, 2003;Lu and Hunter, 2004). Caveolin-1 recruits b-catenin to caveolae membranes for its link with E-cadherin and thus promotes cell adhesion and effectively inhibits b-catenin TCF/LEF-1 signaling (Galbiati et al, 2000;Torres et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…On the other side, caveolin-1 directs the distribution of E-cadherin and increases E-cadherin expression by downregulation of transcriptional repressor snail (Volonte et al, 1999;Lu et al, 2003), and E-cadherin is required for caveolin-1-mediated reduction of b-catenin-TCF/LEF-dependent transcription (Torres et al, 2007). E-cadherin is also known to negatively regulate b-catenin-mediated cell adhesion and transcription by altering its subcellular distribution.…”

Section: Discussionmentioning

confidence: 99%

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

et al. 2008

View full text Add to dashboard Cite

xCT, the functional subunit of the cystine/glutamate transporter xc-system, plays a critical role in the maintenance of intracellular glutathione and redox balance. Disruption of xCT significantly inhibits the growth of a variety of carcinomas, including lymphoma, glioma, prostate and breast cancer. However, the role of xCT in tumor metastasis remains largely unknown. In this study, both xCT þ / þ and xCT À/À melanocytes were used to evaluate the role of xCT in adhesion. xCT activity was suppressed by an inhibitor, sulfasalazine (SASP), or by xCT siRNA in an esophageal cancer cell line, KYSE150. We found that disruption of xCT enhanced homotypic cell-cell adhesion and attenuated cell-extracellular matrix adhesion. SASP significantly inhibited both cell invasion of KYSE150 in vitro and its experimental metastasis in nude mice. Caveolin-1 was upregulated and b-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of b-catenin transcriptional activity. Further study revealed that the upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species-induced p38 MAPK activation. These results first establish the role of xCT in tumor metastasis and implicate a potential target for cancer therapy.

show abstract

Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of β-catenin, and enhanced tumor cell invasion

Cited by 615 publications

References 118 publications

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

Contact Info

Product

Resources

About