Caveolin-1 silencing arrests the proliferation of metastatic lung cancer cells through the inhibition of STAT3 signaling.
ABSTRACT Cav-1 is an essential structural constituent of caveolae implicated in mitogenic signaling, oncogenesis, angiogenesis, neurodegenerative diseases and senescence. Its role as a tumor suppressor gene or as a tumor promoter seems to strictly depend on cell type and tumor stage/grade. The high expression of Cav-1 in some tumors in vivo, amongst which lung adenocarcinoma, is associated with increased tumor aggressiveness, metastatic potential and suppression of apoptosis. In the present study we investigated the role of Cav-1 in metastatic lung cancer proliferation. Cell lines were from metastatic lesions of lung adenocarcinoma (RAL) and of small cell lung carcinoma (SCLC-R1), in which we found Cav-1 expressed at high levels. Results show that siRNA-mediated down-regulation of Cav-1 caused stable arrest of proliferation in both cell lines. A marked reduction of cyclin D1 and of CDK4 expression was evident in the cells transfected with Cav-1 siRNA and consequently of phospho-Rb on ser(795) and ser(780). Furthermore, a significant decrease of the expression of phosphorylated AKT and of its down-stream effectors phosphorylated ERK and STAT3 was evident. Together, these findings indicate that Cav-1 silencing induces an arrest of human metastatic lung proliferation in vitro by a new inhibitory pathway in lung cancer and provide new insights into the molecular mechanisms underlying the pro-survival and tumor-promoting functions of Cav-1.
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ABSTRACT: Signal Transducers and Activators of Transcription (STATs) are a family of transcription factors that regulate cell proliferation, differentiation, apoptosis, immune and inflammatory responses, and angiogenesis. Cumulative evidence has established that STAT3 has a critical role in the development of multiple cancer types. Because it is constitutively activated during disease progression and metastasis in a variety of cancers, STAT3 has promise as a drug target for cancer therapeutics. Recently, STAT3 was found to have an important role in maintaining cancer stem cells in vitro and in mouse tumor models, suggesting STAT3 is integrally involved in tumor initiation, progression and maintenance. STAT3 has been traditionally considered as nontargetable or undruggable, and the lag in developing effective STAT3 inhibitors contributes to the current lack of FDA-approved STAT3 inhibitors. Recent advances in cancer biology and drug discovery efforts have shed light on targeting STAT3 globally and/or specifically for cancer therapy. In this review, we summarize current literature and discuss the potential importance of STAT3 as a novel target for cancer prevention and of STAT3 inhibitors as effective chemopreventive agents.Cancers. 01/2014; 6(2):926-57.
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ABSTRACT: Purpose This study investigated the relationships of caveolin-1 expression with clinical pathologic parameters and the prognosis of patients with large cell lung carcinoma. This study also explored the roles of caveolin-1 in cell invasiveness, matrix metalloproteinase (MMP) expression, and non-small cell lung carcinoma activity in vitro Methods A total of 120 tissue samples were immunohistochemically analyzed for caveolin-1 expression. Cell invasion ability was measured by a Transwell invasion assay. Protein expression was assessed by Western blotting. MMP activity was detected by gelatin zymography Results Caveolin-1 was expressed in 54 of 120 (45.0%) cases of large cell lung carcinoma. Caveolin-1 expression was significantly correlated with node status (N0 vs. N1, N2, and N3; P = 0.005) and advanced pTNM stage (Stages I and II vs. Stage III, P < 0.001). Patients with caveolin-1-positive expression had a poorer prognosis than did those with caveolin-1-negative expression (P < 0.001). The knockdown of caveolin-1 in H460 and 95D cells reduced the invasive ability of the cells and the expression of phosphorylated epidermal growth factor receptor (EGFR), phospho-extracellular signal-regulated kinases 1 and 2, MMP2, and MMP9; the protein level and activity of MMP2 and MMP9 were also decreased by the inhibition of EGFR activity in H460 and 95D cells Conclusions The expression of caveolin-1 was positively correlated with an advanced pathologic stage. Thus, caveolin-1 could act as a predictor of a poor prognosis in patients with large cell lung carcinoma. In addition, the downregulation of caveolin-1 reduced both the invasive ability of tumor cells and the protein and activity levels of MMP2 and MMP9 in vitro, suggesting the involvement of EGFR/MMP signaling in this process.Pathology - Research and Practice 01/2014; · 1.21 Impact Factor
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ABSTRACT: Cancer stem cells (CSCs) may represent targets for carcinogenic initiation by chemical and environmental agents. Recent studies have raised a concern over the potential carcinogenicity of carbon nanotubes (CNTs), one of the most commonly used engineered nanomaterials with asbestos-like properties. Here, we show that chronic (6-month) exposure of human lung epithelial cells to single-walled (SW) CNTs at the workplace-relevant concentration induced an emergence of lung CSCs, as indicated by the induction of CSC tumor spheres and side population (SP). These CSCs, which were found to overexpress tumor promoter caveolin-1 (Cav-1), displayed aggressive cancer phenotypes of apoptosis resistance and enhanced cell invasion and migration compared with their non-CSC counterpart. Using gene manipulation strategies, we reveal for the first time that Cav-1 plays an essential role in CSC regulation and aggressiveness of SWCNT-transformed cells partly through p53 dysregulation, consistent with their suggested role by microarray and gene ontology analysis. Cav-1 not only promoted tumorigenesis in a xenograft mouse model but also metastasis of the transformed cells to neighboring tissues. Since CSCs are crucial to the initiation and early development of carcinogenesis, our findings on CSC induction by SWCNTs and Cav-1 could aid in the early detection and risk assessment of the disease.Oncotarget 05/2014; · 6.64 Impact Factor