AIM1 is an actin-binding protein that suppresses cell migration and micrometastatic dissemination (original) (raw)
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The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion
Molecular oncology, 2017
Experimental and clinical evidence suggests that N-myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1-deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1-deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1-deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1-deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1-deficient cells have restricted actin dynamics, thereby affecting cell migration. These ...
Journal of Bone and Mineral Research, 2009
Bone metastasis is the major cause of mortality associated with prostate cancer. Whereas activin A is known to inhibit prostate cancer cell growth and promote apoptosis, the correlation of elevated activin A with increasing serum prostate-specific antigen (PSA) levels in bone metastatic stages of prostate cancer is well documented. The molecular mechanisms explaining these paradoxical effects of activin A and how activin A influences the progression of prostate cancer with bone metastasis remain unclear. By comparing expression profiles of primary prostate cancer biopsies, with and without bone metastasis, we discovered that the expression of activin A is increased in cases with bone metastatic propensity and correlates with increased androgen receptor (AR), PSA expression, and Gleason scores. Activin A promotes migration of prostate cancer cells to osteoblasts, elevates the AR gene transcription through Smads through binding to AR promoter, and induces nuclear translocation of AR to interact with Smad3. Knockdown of Smad3 by siRNA decreases activin A-promoted AR expression and cancer cell migration. Overexpression of AR reversed Smad3-siRNA suppression on activin A-mediated cell migration to osteoblasts. These data suggest that activation of the AR through Smads is required for activin A-promoted prostate cancer cell migration to bone matrix, thereby promoting the bone metastatic phenotype, and the activin A-Smad-AR axis may be considered a therapeutic target in bone metastatic diseases.
Pseudopodial Actin Dynamics Control Epithelial-Mesenchymal Transition in Metastatic Cancer Cells
Cancer Research, 2010
A key cellular process associated with the invasive or metastatic program in many cancers is the transformation of epithelial cells toward a mesenchymal state, a process called epithelial to mesenchymal transition or EMT. Actin-dependent protrusion of cell pseudopodia is a critical element of mesenchymal cell migration and therefore of cancer metastasis. However, whether EMT occurs in human cancers and, in particular, whether it is a prerequisite for tumor cell invasion and metastasis, remains a subject of debate. Microarray and proteomic analysis of actin-rich pseudopodia from six metastatic human tumor cell lines identified 384 mRNAs and 64 proteins common to the pseudopodia of six metastatic human tumor cell lines of various cancer origins leading to the characterization of 19 common pseudopod-specific proteins. Four of these (AHNAK, septin-9, eIF4E, and S100A11) are shown to be essential for pseudopod protrusion and tumor cell migration and invasion. Knockdown of each of these p...
BMC Cancer, 2014
Background: Understanding the complex, multistep process of metastasis remains a major challenge in cancer research. Metastasis models can reveal insights in tumor development and progression and provide tools to test new intervention strategies. Methods: To develop a new cancer metastasis model, we used DU145 human prostate cancer cells and performed repeated rounds of orthotopic prostate injection and selection of subsequent lymph node metastases. Tumor growth, metastasis, cell migration and invasion were analyzed. Microarray analysis was used to identify cell migration-and cancer-related genes correlating with metastasis. Selected genes were silenced using siRNA, and their roles in cell migration and invasion were determined in transwell migration and Matrigel invasion assays. Results: Our in vivo cycling strategy created cell lines with dramatically increased tumorigenesis and increased ability to colonize lymph nodes (DU145LN1-LN4). Prostate tumor xenografts displayed increased vascularization, enlarged podoplanin-positive lymphatic vessels and invasive margins. Microarray analysis revealed gene expression profiles that correlated with metastatic potential. Using gene network analysis we selected 3 significantly upregulated cell movement and cancer related genes for further analysis: EPCAM (epithelial cell adhesion molecule), ITGB4 (integrin β4) and PLAU (urokinase-type plasminogen activator (uPA)). These genes all showed increased protein expression in the more metastatic DU145-LN4 cells compared to the parental DU145. SiRNA knockdown of EpCAM, integrin-β4 or uPA all significantly reduced cell migration in DU145-LN4 cells. In contrast, only uPA siRNA inhibited cell invasion into Matrigel. This role of uPA in cell invasion was confirmed using the uPA inhibitors, amiloride and UK122. Conclusions: Our approach has identified genes required for the migration and invasion of metastatic tumor cells, and we propose that our new in vivo model system will be a powerful tool to interrogate the metastatic cascade in prostate cancer.
The actin cytoskeleton in normal and pathological cell motility
The International Journal of Biochemistry & Cell Biology, 2004
Cell motility is crucial for tissue formation and for development of organisms. Later on cell migration remains essential throughout the lifetime of the organism for wound healing and immune responses. The actin cytoskeleton is the cellular engine that drives cell motility downstream of a complex signal transduction cascade. The basic molecular machinery underlying the assembly and disassembly of actin filaments consists of a variety of actin binding proteins that regulate the dynamic behavior of the cytoskeleton in response to different signals. The multitude of proteins and regulatory mechanisms partaking in this system makes it vulnerable to mutations and alterations in expression levels that ultimately may cause diseases. The most familiar one is cancer that in later stages is characterized by active aberrant cell migration. Indeed tumor invasion and metastasis are increasingly being associated with deregulation of the actin system.
European Urology Supplements, 2006
Molecular control of CaP onset and progression is still poorly understood. Clusterin (CLU), a widely-distributed protein found overexpressed in regressing prostate following androgen ablation, is suggested to participate in tumour progression. However, its role as pro-or anti-apoptotic factor is still debated. Recently, two related CLU forms have been identified. Full-length CLU enter the endoplasmic reticulum, where is glycosylated and secreted (sCLU); an alternative CLU form, lacking the signal peptide, is synthesized from a second in-frame AUG codon and targeted to the nucleus (nCLU). We studied the differential role of sCLU and nCLU in CaP cells growth and motility. MATERIAL & METHODS: Cell growth (viability), motility (in Boyden's chamber) and cytoskeleton organization (falloidin staining by immunocytochemistry) of androgen-independent prostate cancer PC3 cells and SV40-immortalized, nontumorigenic prostate epithelial PNT1 cells were studied following transient transfection with expression vectors containing full-length CLU cDNA, mainly producing sCLU, or truncated CLU cDNA lacking the leader secretion signal, mainly producing nCLU. CLU protein partners were identified by two-hybrid assay confirmed by co-immunoprecipitation. RESULTS: Both sCLU and nCLU significantly inhibited cell growth of PNT1A cells, while only nCLU affected PC3 cells. Also, motility of PNT1A was significantly decreased by sCLU and nCLU, while only nCLU inhibited the migration of PC3. In both cell lines, the anti-motility effect of nCLU was accompanied by a dramatic remodelling of actin cytoskeleton. We found that nCLU was capable to bind alphaactinin, leading to complete disorganization of the cytoskeleton. We also observed that sCLU, when over-expressed in PNT1A cells, localized in both cytoplasm and nucleus. At difference, sCLU only was found in the cytoplasm of PC3 cells, being nuclear localization negligible. CONCLUSIONS: These data confirm the pro-apoptotic activity of nCLU in both normal and tumoral prostate epithelial cells, also unravelling a novel anti-motility property exerted by this factor by binding to alpha-actinin, a key regulator of actin cytoskeleton structure. We suggest that non-tumorigenic prostate epithelial cells can originate both sCLU and nCLU from the full-length CLU gene, while CaP cells appear to lack this capacity. Therefore, cell-specific changes in the pattern of production of CLU forms might play a crucial role in cell transformation and prostate tumorigenesis.
Seminars in cell & developmental biology, 2017
Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific environments. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that is upregulated in several types of cancers. It shares 86% protein similarity with α-actinin-1, another non-muscle ACTN isoform, which appears to have a more modest role, if any, in cancer progression. While they share regulatory mechanisms, such as phosphorylation, calcium binding, phosphatidyl inositol binding, and calpain cleavage, α-actinin-4 exhibits a unique mechanosensory regulation that α-actinin-1 does not. This behavior is mediated, at least in part, by each protein's actin-binding affinity as well as the catch-slip-bond behavior of the actin binding domains. We will discuss currently known modes of ACTN4 regulation, their interactions, and how mechanosensation may pro...
Cancer Cell, 2006
The expression of podoplanin, a small mucin-like protein, is upregulated in the invasive front of a number of human carcinomas. We have investigated podoplanin function in cultured human breast cancer cells, in a mouse model of pancreatic β cell carcinogenesis, and in human cancer biopsies. Our results indicate that podoplanin promotes tumor cell invasion in vitro and in vivo. Notably, the expression and subcellular localization of epithelial markers are unaltered, and mesenchymal markers are not induced in invasive podoplanin-expressing tumor cells. Rather, podoplanin induces collective cell migration by filopodia formation via the downregulation of the activities of small Rho family GTPases. In conclusion, podoplanin induces an alternative pathway of tumor cell invasion in the absence of epithelial-mesenchymal transition (EMT).
Molecular and cellular endocrinology, 2016
Reproductive hormones influence breast cancer development and progression. While the actions of sex steroids in this setting are established, tentative evidence suggests that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) may also play a role, yet this remains elusive. We here identify that T-47D breast cancer cells express functional receptors for FSH and LH, and that these hormones regulate breast cancer cell motility and invasion through the control of the actin cytoskeleton and the formation of cortical actin aggregates and focal adhesion complexes. Such actions are mediated by the cytoskeletal controllers Moesin and focal adhesion kinase (FAK). Moesin is recruited rapidly by FSH and LH through a signaling cascade requiring the G protein Gα13 and the Rho-associated kinase, ROCK-2. FSH and LH activate FAK via a Gαi/β and c-Src-dependent signaling cascade. Both cascades involve signaling to phosphatidylinositol-3 kinase and Akt. FSH and LH receptors and the relate...