Snail negatively regulates cell adhesion to extracellular matrix and integrin expression via the MAPK pathway in prostate cancer cells

Neal, Corey L.; McKeithen, Danielle; Odero-Marah, Valerie

doi:10.4161/cam.5.3.15618

Cited by 40 publications

(50 citation statements)

References 28 publications

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“…A similar suppressive impact of Snail downregulation on loss of adhesion was obtained using a tetracycline-inducible Snail shRNA system in DU145 cells exposed to 10 Â 2 Gy fIR (Figures 3d and e). Furthermore, genes known to be positively regulated by Snail, such as MMP-7, 18 or negatively, for example, integrin alpha2 (ITGA2 19 ), laminin alpha3 (LAMA3), laminin gamma2 (LAMC2 20 ) and E-cadherin (CDH1 21,22 ) were consistently altered in irradiated non-adherent DU145 cells (Figure 2f), indicating Snail activity. Indeed, knockdown of Snail led to decreased MMP-7 and increased ITGA2, LAMA3, LAMC2 and E-cadherin (Figure 2g).…”

Section: Resultsmentioning

confidence: 97%

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

et al. 2014

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Fractionated ionizing radiation combined with surgery or hormone therapy represents the first-choice treatment for medium to high-risk localized prostate carcinoma. One of the main reasons for the failure of radiotherapy in prostate cancer is radioresistance and further dissemination of surviving cells. In this study, exposure of four metastasis-derived human prostate cancer cell lines (DU145, PC-3, LNCaP and 22RV1) to clinically relevant daily fractions of ionizing radiation (35 doses of 2 Gy) resulted in generation of two radiation-surviving populations: adherent senescent-like cells expressing common senescenceassociated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2 and Nanog. While a subset of the radiation-surviving adherent cells resumed proliferation shortly after completion of the irradiation regimen, the non-adherent cells started to proliferate only on their reattachment several weeks after the radiation-induced loss of adhesion. Like the parental non-irradiated cells, radiation-surviving re-adherent DU145 cells were tumorigenic in immunocompromised mice. The radiation-induced loss of adhesion was dependent on expression of Snail, as siRNA/shRNA-mediated knockdown of Snail prevented cell detachment. On the other hand, survival of the non-adherent cells required active Erk signaling, as chemical inhibition of Erk1/2 by a MEK-selective inhibitor or Erk1/2 knockdown resulted in anoikis-mediated death in the non-adherent cell fraction. Notably, whereas combined inhibition of Erk and PI3K-Akt signaling triggered cell death in the non-adherent cell fraction and blocked proliferation of the adherent population of the prostate cancer cells, such combined treatment had only marginal if any impact on growth of control normal human diploid cells. These results contribute to better understanding of radiation-induced stress response and heterogeneity of human metastatic prostate cancer cells, document treatment-induced plasticity and phenotypically distinct cell subsets, and suggest the way to exploit their differential sensitivity to radiosensitizing drugs in overcoming radioresistance. Cell Death and Differentiation (2015) 22, 898-911; doi:10.1038/cdd.2014.97; published online 11 July 2014Prostate carcinoma (CaP) is the most frequent type of cancer in men, and the sixth cause of cancer-associated death in men worldwide. 1 Despite the advances in diagnosis and therapy of CaP, the mortality has remained almost unchanged for the last decades. Currently, the most successful treatment for localized CaP is prostatectomy with postoperative fractionated radiotherapy, significantly improving metastasis-free and overall survival, where the median of a 15-year survival is around 47% of patients. 2,3 The rest of the patients develop a metastatic disease that is incurable due to the resistance of CaP to androgen ablation, radiotherapy and chemotherapy. Therefore, understanding the mechanisms of radioresistance and chemoresista...

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Section: Resultsmentioning

confidence: 97%

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

et al. 2014

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“…33,55 Snail has also been linked to increased cell invasion in prostate cancer. TGF-β1 has been shown to induce the expression of Snail and cell invasion in prostate cancer cells.…”

Section: Canonical Pathways Of Snail In Prostate Cancermentioning

confidence: 99%

“…63 However, in prostate cancer cells, our data suggest that Snail represses cell adhesion to both fibronectin and collagen. 55 Androgen-independent C4-2 prostate cancer cells, a more aggressive subline of the androgen-dependent LNCaP prostate cancer cells exhibits decreased cell adhesion and increased cell migration to collagen I and fibronectin as compared with LNCaP cells. Stable knockdown of Snail in C4-2 cells increased adhesion and decreased migration, indicating that Snail controls these processes.…”

Section: Non-canonical Pathways Of Snail In Prostate Cancermentioning

confidence: 99%

The role of Snail in prostate cancer

Smith

Odero-Marah²

2012

Cell Adhesion & Migration

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103

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hairpin RNA; VEGF-A, vascular endothelial growth factor-A; NRP1, neuropilin-1; GDF-9, growth and differentiation factor 9; HIF-1a, hypoxia inducible factor 1 a; ERβ1, estrogen receptor β-1; NED, neuroendocrine differentiation; RANKL, receptor activator of NFkB ligand; ROS, reactive oxygen species; GA, gambogic acid; EGCG, epigallocatechin-3-gallate; PTL, sesquiterpene lactone parthenolideProstate cancer is the second most frequently diagnosed cancer and the sixth leading cause of death from cancer in men. Epithelial-mesenchymal transition (EMT) is a process by which cancer cells invade and migrate, and is characterized by loss of cell-cell adhesion molecules such as E-cadherin and increased expression of mesenchymal proteins such as vimentin; EMT is also associated with resistance to therapy. Snail, a master regulator of EMT, has been extensively studied and reported in cancers such as breast and colon; however, its role in prostate cancer is not as widely reported. The purpose of this review is to put together recent facts that summarize Snail signaling in human prostate cancer. Snail is overexpressed in prostate cancer and its expression and activity is controlled via phosphorylation and growth factor signaling. Snail is involved in its canonical role of inducing EMT in prostate cancer cells; however, it plays a role in non-canonical pathways that do not involve EMT such regulation of bone turnover and neuroendocrine differentiation. Thus, studies indicate that Snail signaling contributes to prostate cancer progression and metastasis and therapeutic targeting of Snail in prostate cancer holds promise in future.

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“…This is accompanied by the loss of markers of epithelial phenotype and gain of mesenchymal markers. Profiling of expression of α 2 and α 6 integrin expression and EMT in prostate tumours has only recently been examined (Neal et al, 2011). SNAIL, a key factor promoting EMT decreases cell adhesion and increases α 2 and β 1 expression (Neal et al, 2011).…”

Section: Integrin α 2 and α 6 In Stem Cellsmentioning

confidence: 99%

“…Profiling of expression of α 2 and α 6 integrin expression and EMT in prostate tumours has only recently been examined (Neal et al, 2011). SNAIL, a key factor promoting EMT decreases cell adhesion and increases α 2 and β 1 expression (Neal et al, 2011). However, there is evidence that known regulators of EMT, for example ZEB1 influence expression of ITGB4 (Drake et al, 2010), and down-regulation of α 6 β 4 in the prostate cancer cell line SNAI2 knockdown studies in PC3 cells (Emadi Baygi et al, 2010) However, EMT in prostate cancer remains controversial.…”

Section: Integrin α 2 and α 6 In Stem Cellsmentioning

confidence: 99%

Integrins as Determinants of Genetic Susceptibility, Tumour Behaviour and Their Potential as Therapeutic Targets

Marthick¹,

Holloway²,

Dickinson³

2011

Prostate Cancer - From Bench to Bedside

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Snail negatively regulates cell adhesion to extracellular matrix and integrin expression via the MAPK pathway in prostate cancer cells

Cited by 40 publications

References 28 publications

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

The role of Snail in prostate cancer

Integrins as Determinants of Genetic Susceptibility, Tumour Behaviour and Their Potential as Therapeutic Targets

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