Lysophosphatidic Acid Upregulates Recepteur D’origine Nantais Expression and Cell Invasion via Egr-1, AP-1, and NF-κB Signaling in Bladder Carcinoma Cells

Muscle invasive bladder carcinoma is a highly malignant cancer with a high mortality rate, due to its tendency to metastasize. The tyrosine kinase recepteur d’origine nantais (RON) promotes bladder carcinoma metastasis. Lysophosphatidic acid (LPA) is a phospholipid derivative, which acts as a signaling molecule to activate three high affinity G-protein coupled receptors, LPA1, LPA2, and LPA3. This in turn leads to cell proliferation and contributes to oncogenesis. However, little is known about the effects of LPA on invasive bladder cancer (IBC). In this study, we discovered that LPA upregulated RON expression, which in turn promoted cell invasion in bladder cancer T24 cells. As expected, we found that the LPA receptor was essential for the LPA induced increase in RON expression. More interestingly, we discovered that LPA induced RON expression via the MAPK (ERK1/2, JNK1/2), Egr-1, AP-1, and NF-κB signaling axes. These results provide experimental evidence and novel insights regarding bladder malignancy metastasis, which could be helpful for developing new therapeutic strategies for IBC treatment.

Download Full-text

Bladder Cancer Metastasis Induced by Chronic Everolimus Application Can Be Counteracted by Sulforaphane In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21155582 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5582

Author(s):

Saira Justin ◽

Jochen Rutz ◽

Sebastian Maxeiner ◽

Felix K.-H. Chun ◽

Eva Juengel ◽

...

Keyword(s):

Bladder Cancer ◽

Bladder Carcinoma ◽

Cancer Metastasis ◽

Chemotactic Activity ◽

Carcinoma Cells ◽

Down Regulation ◽

Knock Down ◽

Tumor Dissemination ◽

Bladder Carcinoma Cells

Chronic treatment with the mTOR inhibitor, everolimus, fails long-term in preventing tumor growth and dissemination in cancer patients. Thus, patients experiencing treatment resistance seek complementary measures, hoping to improve therapeutic efficacy. This study investigated metastatic characteristics of bladder carcinoma cells exposed to everolimus combined with the isothiocyanate sulforaphane (SFN), which has been shown to exert cancer inhibiting properties. RT112, UMUC3, or TCCSUP bladder carcinoma cells were exposed short- (24 h) or long-term (8 weeks) to everolimus (0.5 nM) or SFN (2.5 µM), alone or in combination. Adhesion and chemotaxis along with profiling details of CD44 receptor variants (v) and integrin α and β subtypes were evaluated. The functional impact of CD44 and integrins was explored by blocking studies and siRNA knock-down. Long-term exposure to everolimus enhanced chemotactic activity, whereas long-term exposure to SFN or the SFN-everolimus combination diminished chemotaxis. CD44v4 and v7 increased on RT112 cells following exposure to SFN or SFN-everolimus. Up-regulation of the integrins α6, αV, and β1 and down-regulation of β4 that was present with everolimus alone could be prevented by combining SFN and everolimus. Down-regulation of αV, β1, and β4 reduced chemotactic activity, whereas knock-down of CD44 correlated with enhanced chemotaxis. SFN could, therefore, inhibit resistance-related tumor dissemination during everolimus-based bladder cancer treatment.

Download Full-text

Induction of Mitotic Catastrophe via Inhibition of Aurora B by Ionizing Radiation With Additive of Mulberry Water Extract in Human Bladder Cancer Cells

Integrative Cancer Therapies ◽

10.1177/1534735418808586 ◽

2018 ◽

Vol 18 ◽

pp. 153473541880858 ◽

Cited By ~ 1

Author(s):

Chia-Cheng Su ◽

Nien-Cheng Chen ◽

Charng-Cherng Chyau ◽

Hsien-Chun Tseng ◽

Fen-Pi Chou

Keyword(s):

Bladder Cancer ◽

Bladder Carcinoma ◽

Water Extract ◽

Carcinoma Cells ◽

Mitotic Catastrophe ◽

Aurora B ◽

Phase Arrest ◽

Bladder Cancer Cells ◽

M Phase ◽

Bladder Carcinoma Cells

Mulberry fruit water extract (MWE) has been reported to synergistically enhance the cytotoxic effect of paclitaxel by promoting mitotic catastrophe to induce apoptosis in bladder cancer cells in our previous work. The aim of this study was to evaluate and to mechanistically explore the effects of MWE on bladder cancer responses to ionizing radiation (IR) by treating TSGH 8301 bladder carcinoma cells with MWE after exposing to IR. The results of MTT assay showed a synergistic cytotoxicity of IR with the co-treatment of MWE (IR/MWE) by inducing G2/M phase arrest as demonstrated by flow cytometry analysis in TSGH 8301, HT1367 and HT1197 bladder carcinoma cells lines. The IR/MWE-treated cells expressed increased levels of the G2/M phase arrest-related proteins cdc2/cyclin B1 and displayed giant multinucleated morphology, a typical characteristic of mitotic catastrophe. Immunofluorescent confocal microscopy revealed that the combined strategy inhibited Aurora B phosphorylation through Ras/Raf/MEK/ERK signaling cascade as demonstrated by Western blotting analysis. IR/MWE also caused an inhibitory effect on Plk1 and the subsequent downstream regulator RhoA repression and Cep55 induction, which would influence cell cycle progression in the early steps of cytokinesis. A profound tumor growth suppression and inactivation of Aurora B activity in the tumor tissues by IR/MWE treatment were confirmed in the TSGH 8301 xenograft model in vivo. These data demonstrated that MWE could be an effective auxiliary to synergize with radiation on the anticancer efficacy by promoting mitotic catastrophe through inhibition of Aurora B, providing a novel and effective therapeutic option for bladder cancer management.

Download Full-text

G-protein-coupled receptor signaling and polarized actin dynamics drive cell-in-cell invasion

eLife ◽

10.7554/elife.02786 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 31

Author(s):

Vladimir Purvanov ◽

Manuel Holst ◽

Jameel Khan ◽

Christian Baarlink ◽

Robert Grosse

Keyword(s):

G Protein ◽

Cell Invasion ◽

Carcinoma Cells ◽

Actin Dynamics ◽

Specific Cell ◽

Lpa Receptor ◽

Surface Receptors ◽

Actin Structure ◽

Independent Process ◽

G Protein Coupled

Homotypic or entotic cell-in-cell invasion is an integrin-independent process observed in carcinoma cells exposed during conditions of low adhesion such as in exudates of malignant disease. Although active cell-in-cell invasion depends on RhoA and actin, the precise mechanism as well as the underlying actin structures and assembly factors driving the process are unknown. Furthermore, whether specific cell surface receptors trigger entotic invasion in a signal-dependent fashion has not been investigated. In this study, we identify the G-protein-coupled LPA receptor 2 (LPAR2) as a signal transducer specifically required for the actively invading cell during entosis. We find that G12/13 and PDZ-RhoGEF are required for entotic invasion, which is driven by blebbing and a uropod-like actin structure at the rear of the invading cell. Finally, we provide evidence for an involvement of the RhoA-regulated formin Dia1 for entosis downstream of LPAR2. Thus, we delineate a signaling process that regulates actin dynamics during cell-in-cell invasion.

Download Full-text

874 MIRNA PROFILES IN BLADDER CARCINOMA CELLS LINKED TO EPITHELIAL-MESENCHYMAL TRANSITION (EMT) AND DIFFERENT BIOMARKER PROTEINS IN BLADDER CANCER

The Journal of Urology ◽

10.1016/j.juro.2011.02.698 ◽

2011 ◽

Vol 185 (4S) ◽

Author(s):

Niall J. Harty ◽

Spencer I. Kozinn ◽

Jessica M. DeLong ◽

Christina S. Deliyiannis ◽

Kimberly M. Rieger-Christ ◽

...

Keyword(s):

Bladder Cancer ◽

Bladder Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cells ◽

Mesenchymal Transition ◽

Bladder Carcinoma Cells

Download Full-text

Maspin is a PTEN-Upregulated and p53-Upregulated Tumor Suppressor Gene and Acts as an HDAC1 Inhibitor in Human Bladder Cancer

Cancers ◽

10.3390/cancers12010010 ◽

2019 ◽

Vol 12 (1) ◽

pp. 10 ◽

Cited By ~ 2

Author(s):

Yu-Hsiang Lin ◽

Ke-Hung Tsui ◽

Kang-Shuo Chang ◽

Chen-Pang Hou ◽

Tsui-Hsia Feng ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Suppressor ◽

Bladder Carcinoma ◽

Suppressor Gene ◽

Carcinoma Cells ◽

Human Bladder ◽

Maspin Expression ◽

Bladder Carcinoma Cells

Maspin is a member of the clade B serine protease inhibitor superfamily and exhibits diverse regulatory effects in various types of solid tumors. We compared the expressions of maspin and determined its potential biological functions and regulatory mechanisms in bladder carcinoma cells in vitro and in vivo. The results of RT-qPCR indicated that maspin expressed significantly lower levels in the bladder cancer tissues than in the paired normal tissues. The immunohistochemical assays of human bladder tissue arrays revealed similar results. Maspin-knockdown enhanced cell invasion whereas the overexpression of maspin resulted in the opposite process taking place. Knockdown of maspin also enhanced tumorigenesis in vivo and downregulated protein levels of acetyl-histone H3. Moreover, in bladder carcinoma cells, maspin modulated HDAC1 target genes, including cyclin D1, p21, MMP9, and vimentin. Treatment with MK2206, which is an Akt inhibitor, upregulated maspin expression, whereas PTEN-knockdown or PTEN activity inhibitor (VO-OHpic) treatments demonstrated reverse results. The ectopic overexpression of p53 or camptothecin treatment induced maspin expression. Our study indicated that maspin is a PTEN-upregulated and p53-upregulated gene that blocks cell growth in vitro and in vivo, and may act as an HDAC1 inhibitor in bladder carcinoma cells. We consider that maspin is a potential tumor suppressor gene in bladder cancer.

Download Full-text

Complications of intravesical BCG therapy in non-muscle invasive bladder cancer: our tertiary care centre experience

African Journal of Urology ◽

10.1186/s12301-020-00099-6 ◽

2020 ◽

Vol 26 (1) ◽

Author(s):

Vivek Sharma ◽

Avinash P. S. Thakur ◽

Vasantharaja Ramasamy ◽

Pushpendra Kumar Shukla ◽

Fanindra Singh Solanki ◽

...

Keyword(s):

Bladder Cancer ◽

Adverse Effects ◽

Bladder Carcinoma ◽

Bladder Tumour ◽

The Body ◽

Bcg Therapy ◽

Intravesical Bcg ◽

Urothelial Bladder ◽

Muscle Invasive ◽

Intravesical Bcg Therapy

Abstract Background Urothelial bladder carcinoma accounts for around 3.9% cases of all the male cancers in India. Non-muscle-invasive bladder carcinoma (NMIBC) is predominant group which constitute approximately three fourth of the urothelial bladder cancer. Intravesical BCG immunotherapy is the corner stone of today’s NMIBC management. However, as with any other therapy it has its own complications and its interruption due to these adverse effects is a major cause of suboptimal efficacy. The aim of this study was to assess the complications of intravesical BCG therapy and their management in NMIBC patients. Methods This was a retrospective descriptive study conducted between October 2016 and November 2019; a backward review of 149 patients with diagnosis of NMIBC that undergone intravesicle BCG therapy was performed. Patient’s demographical, clinical, diagnostic and procedural data regarding bladder tumour, BCG therapy, its complications and management were collected and analysed. Results Total 149 patients were analysed, comprising 116 males and 33 females. The mean age was of 57.2 ± 6.7 years. Total 85.23% were primary and 14.76% were recurrent tumours. Total 96 patients (64.42%) completed the planned course, while 53 (35.57%) interrupted. The reasons for BCG interruption includes adverse effects (15.4%), progression of disease (6.7%), disease refractory to BCG (4.6%) and disease recurrence during BCG (3.3%). Most of the adverse events occurred in first 6 months and most interruptions occurred after the induction period. Cystitis was the most common observed adverse effect seen in 39.6% patients. Frequency, urgency, haematuria were common presentation. Radical cystectomy was the most common (16.10%) further treatment with patients whose treatment was interrupted. Conclusion BCG is an indispensable therapy available for NMIBC, but it is associated with array of adverse effects and complications, which are the main reasons for poor compliance to BCG therapy. Although BCG-related complications can affect any organ in the body, potentially life-threatening systemic BCG-related infections are encountered in only < 5% of patients. There are some difficulties in diagnosis of the BCG complications because acid-fast staining, culture and PCR test are not always positive; tissue biopsies should be indicated sometimes to evaluate histopathology and presence of M. bovis. A persistently monitored multidisciplinary approach with high index of suspicion and prompt anti-TB therapy can help to derive the maximum benefits while keeping the complications at check.

Download Full-text