Caveolin-1-enhanced motility and focal adhesion turnover require tyrosine-14 but not accumulation to the rear in metastatic cancer cells. PLoS One 7 (original) (raw)
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Caveolin-1 in Cell Migration and Metastasis
Current Molecular Medicine, 2014
Caveolin-1 is a member of the caveolin family that has been ascribed a dual role in cancer. In early stages of disease the protein functions predominantly as a tumor suppressor, whereas at later stages, caveolin-1 expression is associated with tumor progression and metastasis. Here, some mechanisms associated with caveolin-1-dependent tumor suppression will be briefly discussed before focusing on the role of this protein and particularly phosphorylation of tyrosine-14 in promoting cell migration, invasion and metastasis. Models are provided summarizing possible explanations for these dramatic changes in function, as well as mechanisms by which this may be achieved.
Oncotarget, 2017
Expression of the scaffolding protein Caveolin-1 (CAV1) enhances migration and invasion of metastatic cancer cells. Yet, CAV1 also functions as a tumor suppressor in early stages of cancer, where expression is suppressed by epigenetic mechanisms. Thus, we sought to identify stimuli/mechanisms that revert epigenetic CAV1 silencing in cancer cells and evaluate how this affects their metastatic potential. We reasoned that restricted tissue availability of anti-neoplastic drugs during chemotherapy might expose cancer cells to sub-therapeutic concentrations, which activate signaling pathways and the expression of CAV1 to favor the acquisition of more aggressive traits. Here, we used in vitro [2D, invasion] and in vivo (metastasis) assays, as well as genetic and biochemical approaches to address this question. Colon and breast cancer cells were identified where CAV1 levels were low due to epigenetic suppression and could be reverted by treatment with the methyltransferase inhibitor 5'...
Oncotarget, 2016
Caveolin-1 (CAV1) is a scaffolding protein that plays a dual role in cancer. In advanced stages of this disease, CAV1 expression in tumor cells is associated with enhanced metastatic potential, while, at earlier stages, CAV1 functions as a tumor suppressor. We recently implicated CAV1 phosphorylation on tyrosine 14 (Y14) in CAV1-enhanced cell migration. However, the contribution of this modification to the dual role of CAV1 in cancer remained unexplored. Here, we used in vitro [2D and transendothelial cell migration (TEM), invasion] and in vivo (metastasis) assays, as well as genetic and biochemical approaches to address this question in B16F10 murine melanoma cells. CAV1 promoted directional migration on fibronectin or laminin, two abundant lung extracellular matrix (ECM) components, which correlated with enhanced Y14 phosphorylation during spreading. Moreover, CAV1-driven migration, invasion, TEM and metastasis were ablated by expression of the phosphorylation null CAV1(Y14F), but not the phosphorylation mimicking CAV1(Y14E) mutation. Finally, CAV1-enhanced focal adhesion dynamics and surface expression of beta1 integrin were required for CAV1-driven TEM. Importantly, CAV1 function as a tumor suppressor in tumor formation assays was not altered by the Y14F mutation. In conclusion, our results provide critical insight to the mechanisms of CAV1 action during cancer development. Specific ECM-integrin interactions and Y14 phosphorylation are required for CAV1-enhanced melanoma cell migration, invasion and metastasis to the lung. Because Y14F mutation diminishes metastasis without inhibiting the tumor suppressor function of CAV1, Y14 phosphorylation emerges as an attractive therapeutic target to prevent metastasis without altering beneficial traits of CAV1.
Journal of Biological Chemistry, 2000
Caveolin-1 is a principal component of caveolae membranes that may function as a transformation suppressor. For example, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (D7S522; 7q31.1) that is deleted in human cancers, including mammary carcinomas. However, little is known about the role of caveolins in regulating cell movement, a critical parameter in determining metastatic potential. Here, we examine the role of caveolin-1 in cell movement. For this purpose, we employed an established cellular model, MTLn3, a metastatic rat mammary adenocarcinoma cell line. In this system, epidermal growth factor (EGF) stimulation induces rapid lamellipod extension and cell migration. Interestingly, we find that MTLn3 cells fail to express detectable levels of endogenous caveolin-1. To restore caveolin-1 expression in MTLn3 cells efficiently, we employed an inducible adenoviral gene delivery system to achieve tightly controlled expression of caveolin-1. We show here that caveolin-1 expression in MTLn3 cells inhibits EGF-stimulated lamellipod extension and cell migration and blocks their anchorage-independent growth. Under these conditions, EGF-induced activation of the p42/44 mitogen-activated protein kinase cascade is also blunted. Our results suggest that caveolin-1 expression in motile MTLn3 cells induces a non-motile phenotype.
The non-receptor tyrosine phosphatase type 14 blocks caveolin-1-enhanced cancer cell metastasis
Oncogene
Caveolin-1 (CAV1) enhanced migration, invasion, and metastasis of cancer cells is inhibited by co-expression of the glycoprotein E-cadherin. Although the two proteins form a multiprotein complex that includes β-catenin, it remained unclear how this would contribute to blocking the metastasis promoting function of CAV1. Here, we characterized by mass spectrometry the protein composition of CAV1 immunoprecipitates from B16F10 murine melanoma cells expressing or not E-cadherin. The novel protein tyrosine phosphatase PTPN14 was identified by mass spectrometry analysis exclusively in co-immunoprecipitates of CAV1 with E-cadherin. Interestingly, PTPN14 is implicated in controlling metastasis, but only few known PTPN14 substrates exist. We corroborated by western blotting experiments that PTPN14 and CAV1 co-inmunoprecipitated in the presence of E-cadherin in B16F10 melanoma and other cancer cells. Moreover, the CAV1(Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in...
Caveolin-1 as a promoter of tumour spreading: when, how, where and why
Journal of Cellular and Molecular Medicine, 2013
Caveolae are non-clathrin invaginations of the plasma membrane in most cell types; they are involved in signalling functions and molecule trafficking, thus modulating several biological functions, including cell growth, apoptosis and angiogenesis. The major structural protein in caveolae is caveolin-1, which is known to act as a key regulator in cancer onset and progression through its role as a tumour suppressor. Caveolin-1 can also promote cell proliferation, survival and metastasis as well as chemo-and radioresistance. Here, we discuss recent findings and novel concepts that support a role for caveolin-1 in cancer development and its distant spreading. We also address the potential application of caveolin-1 in tumour therapy and diagnosis.
Caveolin-1 in oncogenic transformation, cancer, and metastasis
AJP: Cell Physiology, 2004
Caveolae are 50- to 100-nm omega-shaped invaginations of the plasma membrane that function as regulators of signal transduction. Caveolins are a class of oligomeric structural proteins that are both necessary and sufficient for caveolae formation. Interestingly, caveolin-1 has been implicated in the pathogenesis of oncogenic cell transformation, tumorigenesis, and metastasis. Here, we review the available experimental evidence (gleaned from cultured cells, animal models, and human tumor samples) that caveolin-1 (Cav-1) functions as a “tumor and/or metastasis modifier gene.” Genetic evidence from the study of Cav-1(−/−) null mice and human breast cancer mutations [CAV-1 (P132L)] supports the idea that caveolin-1 normally functions as a negative regulator of cell transformation and mammary tumorigenesis. In contrast, caveolin-1 may function as a tumor promoter in prostate cancers. We discuss possible molecular mechanisms to explain these intriguing, seemingly opposing, findings. More ...
American Journal of Pathology, 2002
Caveolin-1 , a 21-to 24-kd integral membrane protein, is primarily implicated as a tumor suppressor gene. Transformed cells normally contain reduced or no caveolin-1. Re-expression of caveolin-1 is found in advanced human and mouse prostate adenocarcinomas. To explore its potential role in tumorigenesis and tumor progression of human lung cancers, we used the well-characterized cell line (CL) series of lung adenocarcinoma cells with increasing cellular invasiveness to show that expression of caveolin-1 mRNA and protein was up-regulated with enhanced invasion/metastatic capability of CL cells. Reintroducing the caveolin-1 gene into the less invasive , caveolin-1-negative CL cells enhanced their invasive capability at least by twofold , as revealed by an in vitro chamber invasion assay. Thus , a correlation exists for both constitutive and induced expression of caveolin-1 in CL cells. Immunohistochemical examination of caveolin-1 was performed in 95 specimens obtained retrospectively from patients who had lung adenocarcinoma either with (35 patients) or without (60 patients) ipsilateral hilar/peribronchial tumormetastasized lymph nodes. Caveolin-1 immunoreactivity was either totally absent or just barely detectable in a few lung adenocarcinoma cells from cases diagnosed as lung adenocarcinoma without regional lymph node metastasis. In contrast , increased caveolin-1 immunoreactivity both in number and intensity was detected in primary lung adenocarcinoma cells as well as in cancer cells that metastasized to regional lymph nodes from the cases diagnosed as advanced lung adenocarcinoma with nodal metastases. Multivariate analysis considering caveolin-1 immunoreactivity in addition to the established prognostic parameters such as pT stage , pN in these patients confirmed that caveolin-1 is an independent functional predictor of poor survival. We further revealed that up-regulated caveolin-1 in CL cells is necessary for mediating filopodia formation , which may enhance the invasive ability of lung adenocarcinoma cells. Caveolin-1, a 21-to 24-kd protein, is the principal component of caveolae, which are special invaginated microdomains of the plasma membrane present in most mammalian cells. 1 It is well established that caveolin-1 is a tumor suppressor gene. Caveolin-1 mRNA and protein expression are frequently lost in human cancer cell lines. Re-expression of caveolin-1 in oncogenically transformed cell lines inhibits tumor cell growth and reduces tumorigenicity. 2-6 Several mechanisms have been proposed for caveolin-1 to function as a tumor suppressor. Caveolin-1 may exert its tumor-growth inhibition by contact inactivation of signaling molecules such as v-src, Ha-Ras, protein kinase A, PKC, and p42/44 MAP kinase within caveolae. 7-10 In addition, down-regulation of caveolin-1 in colon carcinoma cells has been shown to prevent the degradation of inducible nitric oxide synthase via the proteosome pathway, which, in turn, increases the local nitric oxide concentration to facilitate tumorigenesis. Caveolin-1 can also function as a tumor metastasispromoting molecule, which is unrelated to its obvious function of cell growth inhibition. 12 Elevated expression of caveolin-1 is found to be associated with progression of prostate, colon, and breast carcinoma. 13,14 Inhibition of c-myc-induced apoptosis by caveolin-1 was recently proposed to promote progression of prostate cancer, 15 and it may serve as a prognostic indicator for these patients. Nonetheless, it still remains unclear whether and how caveolin-1 can potentiate tumor progression in other types of human cancer.