Wnt/β-Catenin Signaling Contributes to Paclitaxel Resistance in Bladder Cancer Cells with Cancer Stem Cell-Like Properties

The Wnt/β-catenin pathway plays an important role in tumor progression and chemotherapy resistance and seems to be essential for the maintenance of cancer stem cells (CSC) in several tumor types. However, the interplay of these factors has not been fully addressed in bladder cancer. Here, our goal was to analyze the role of the Wnt/β-catenin pathway in paclitaxel resistance and to study the therapeutic efficacy of its inhibition in bladder cancer cells, as well as to determine its influence in the maintenance of the CSC-like phenotype in bladder cancer. Our results show that paclitaxel-resistant HT1197 cells have hyperactivation of the Wnt/β-catenin pathway and increased CSC-like properties compared with paclitaxel-sensitive 5637 cells. Paclitaxel sensitivity diminishes in 5637 cells after β-catenin overexpression or when they are grown as tumorspheres, enriched for the CSC-like phenotype. Additionally, downregulation of β-catenin or inhibition with XAV939 sensitizes HT1197 cells to paclitaxel. Moreover, a subset of muscle-invasive bladder carcinomas shows aberrant expression of β-catenin that associates with positive expression of the CSC marker ALDH1A1. In conclusion, we demonstrate that Wnt/β-catenin signaling contributes to paclitaxel resistance in bladder cancer cells with CSC-like properties.

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Role of heat shock protein 90 inhibition with 17-(allylamino)-17 (demethoxygeldenamycin) in muscle-invasive bladder cancer cells.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.273 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 273-273

Author(s):

H. Williams

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Intracellular Signaling ◽

Heat Shock Protein 90 ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Bladder Cancer Cells ◽

Muscle Invasive

273 Background: Muscle invasive bladder cancer portends a poor long term prognosis. Platinum based therapy is the mainstay of treatment but more effective agents are needed for management of this disease. Heat shock protein 90 (Hsp90) is a ubiquitous protein that has been shown to be overexpressed in tumor cells. It functions as a molecular chaperone responsible for the stability and function of a number of proteins critical to the oncogenic process. 17-(allylamino)-17 demethoxygeldanamycin (17 AAG) is a Hsp90 inhibitor that is currently in phase III trials in several tumor models. The purpose of this study was to evaluate the role of 17 AAG treatment for bladder cancer in vitro. Methods: Seven bladder cancer cell lines representing muscle invasive bladder cancer were treated in the presence and absence of 17 AAG. Both short term and long term treatments were evaluated for their effects on growth, motility and invasion of the cancer cells. Expression of proteins involved in cell growth, survival and metastasis were evaluated with Western blotting. Results: Our data demonstrated that 17 AAG treatment resulted in induction of apoptosis, inhibition of cell cycle progression through inhibition of MAP kinase pathway and cyclin D1 expression. Decreased tumor cell motility and invasion was observed with 17 AAG treatment. Several intracellular signaling pathways involved in cell proliferation, invasion and metastasis were inhibited. Conclusions: Hsp90 inhibition in muscle invasive bladder cancer cells impacts growth, motility and invasiveness by inhibiting numerous intracellular signaling pathways. Taken together, these findings suggest a possible role for Hsp90 inhibitors in bladder cancer tumorigenesis. No significant financial relationships to disclose.

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792: Role of Oxidative Stress in Tumorigenic Potential of Bladder Cancer Cells

The Journal of Urology ◽

10.1016/s0022-5347(18)34961-9 ◽

2005 ◽

Vol 173 (4S) ◽

pp. 214-215 ◽

Cited By ~ 2

Author(s):

Daniel Cho ◽

Xiao Fang Ha ◽

J. Andre Melendez ◽

Louis J. Giorgi ◽

Badar M. Mian

Keyword(s):

Oxidative Stress ◽

Bladder Cancer ◽

Cancer Cells ◽

Tumorigenic Potential ◽

Bladder Cancer Cells

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Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells

Cancers ◽

10.3390/cancers10120490 ◽

2018 ◽

Vol 10 (12) ◽

pp. 490 ◽

Cited By ~ 8

Author(s):

Rocío Jiménez-Guerrero ◽

Jessica Gasca ◽

M. Flores ◽

Begoña Pérez-Valderrama ◽

Cristina Tejera-Parrado ◽

...

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Cancer Cells ◽

Autophagic Flux ◽

Paclitaxel Resistance ◽

Mitotic Slippage ◽

Apoptotic Protein ◽

Clinical Benefits ◽

Induced Apoptosis ◽

Bladder Carcinomas

Paclitaxel is a treatment option for advanced or metastatic bladder cancer after the failure of first-line cisplatin and gemcitabine, although resistance limits its clinical benefits. Mcl-1 is an anti-apoptotic protein that promotes resistance to paclitaxel in different tumors. Obatoclax, a BH3 mimetic of the Bcl-2 family of proteins, antagonizes Mcl-1 and hence may reverse paclitaxel resistance in Mcl-1-overexpressing tumors. In this study, paclitaxel-sensitive 5637 and -resistant HT1197 bladder cancer cells were treated with paclitaxel, obatoclax, or combinations of both. Apoptosis, cell cycle, and autophagy were measured by Western blot, flow cytometry, and fluorescence microscopy. Moreover, Mcl-1 expression was analyzed by immunohistochemistry in bladder carcinoma tissues. Our results confirmed that paclitaxel alone induced Mcl-1 downregulation and apoptosis in 5637, but not in HT1197 cells; however, combinations of obatoclax and paclitaxel sensitized HT1197 cells to the treatment. In obatoclax-treated 5637 and obatoclax + paclitaxel-treated HT1197 cells, the blockade of the autophagic flux correlated with apoptosis and was associated with caspase-dependent cleavage of beclin-1. Obatoclax alone delayed the cell cycle in 5637, but not in HT1197 cells, whereas combinations of both retarded the cell cycle and reduced mitotic slippage. In conclusion, obatoclax sensitizes HT1197 cells to paclitaxel-induced apoptosis through the blockade of the autophagic flux and effects on the cell cycle. Furthermore, Mcl-1 is overexpressed in many invasive bladder carcinomas, and it is related to tumor progression, so Mcl-1 expression may be of predictive value in bladder cancer.

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Generation of potent cytotoxic T lymphocytes against in male patients with non-muscle invasive bladder cancer by dendritic cells loaded with dying T24 bladder cancer cells

International braz j urol ◽

10.1590/s1677-5538.ibju.2016.0274 ◽

2017 ◽

Vol 43 (4) ◽

pp. 615-627 ◽

Cited By ~ 3

Author(s):

Eu Chang Hwang ◽

Seung Il Jung ◽

Hyun-Ju Lee ◽

Je-Jung Lee ◽

Dong Deuk Kwon

Keyword(s):

Bladder Cancer ◽

Dendritic Cells ◽

T Lymphocytes ◽

Cancer Cells ◽

Cytotoxic T Lymphocytes ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Bladder Cancer Cells ◽

Male Patients ◽

Muscle Invasive

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514 Role of macroautophagy in the response of bladder cancer cells to the pan Bcl-2 inhibitor AT-101 (Gossypol)

European Urology Supplements ◽

10.1016/s1569-9056(14)60506-6 ◽

2014 ◽

Vol 13 (1) ◽

pp. e514

Author(s):

J. Mani ◽

S. Vallo ◽

S. Rakel ◽

P. Antonietti ◽

G. Bartsch ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Bladder Cancer Cells

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ROLE OF MITOCHONDRIA IN CIPROFLOXACIN INDUCED APOPTOSIS IN BLADDER CANCER CELLS

The Journal of Urology ◽

10.1016/s0022-5347(05)65283-4 ◽

2002 ◽

Vol 167 (3) ◽

pp. 1288-1294 ◽

Cited By ~ 21

Author(s):

OLIVIA ARANHA ◽

LIPING ZHU ◽

SAMIR ALHASAN ◽

DAVID P. WOOD ◽

TUAN H. KUO ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Bladder Cancer Cells ◽

Induced Apoptosis

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The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells

Carcinogenesis ◽

10.1093/carcin/21.5.403 ◽

2000 ◽

Vol 21 (7) ◽

pp. 1403-1409 ◽

Cited By ~ 4

Author(s):

Erik M. Grossman ◽

Walter E. Longo ◽

Ninder Panesar ◽

John E. Mazuski ◽

Donald L. Kaminski

Keyword(s):

Bladder Cancer ◽

Gall Bladder ◽

Cancer Cells ◽

Gall Bladder Cancer ◽

Bladder Cancer Cells

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Notch-3 promote angiogenesis and proliferation of bladder cancer cells through the PI3K/Akt pathway

American Journal of BioMedicine ◽

10.18081/2333-5106/016-314-328 ◽

2016 ◽

Vol 4 (3) ◽

pp. 314-328

Author(s):

Joan V. Draucker ◽

Irene Talarico

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Transitional Cell ◽

Frozen Storage ◽

Benign Prostatic Hypertrophy ◽

Akt Pathway ◽

Bladder Cancer Patient ◽

Notch 3 ◽

Bladder Cancer Cells ◽

Muscle Invasive

Transitional cell carcinoma (TCC) of the bladder is the most common form of bladder cancer and is manifested in two distinct forms with different clinical and biological behaviors. Approximately 70% of patients present with non-muscle invasive tumors, while the remaining 30% present with muscle-invasive tumors. Despite good prognosis for patients with superficial disease, recurrence is common and is associated with development of muscle-invasive disease. Seventy seven tissue specimens from bladder cancer patient [32- noninvasive and 45- muscle invasive] and forty specimens from patients with benign prostatic hypertrophy as control were enrolled. The specimen’s tissue was halved into either in 10% neutral buffered formalin for histological process or snap frozen storage in liquid nitrogen. Tissue RNA and protein were examined by qPCR and western blot for Noch-3 and PI3K/Akt pathway respectively. One-Way ANOVA with Bonferroni tests was applied, with significance accepted at P<0.05. Our results highlight critical, overlooked functions for Notch-3 in regulating angiogenesis and proliferation of bladder cancer cells and suggest that Notch-3 inhibitor may be drug target in bladder cancer. Further investigation into the precise mechanism for this protection is warranted.

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The role of HIF-1α in regulating NLRP3 inflammasome activation in bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17028 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17028-e17028 ◽

Cited By ~ 1

Author(s):

Yuan-Ru Chen ◽

Hsin-Chih Yeh ◽

Fang-Yen Chiu ◽

Hsin-En Wu ◽

Huei-Chen Fang ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Cancer Cells ◽

Nlrp3 Inflammasome ◽

Migration And Invasion ◽

Inflammasome Activation ◽

T24 Cells ◽

Nlrp3 Inflammasome Activation ◽

Bladder Cancer Cells

e17028 Background: Bladder cancer is one of the most common malignancies of urinary system with the forth incidence rate and the eighth leading mortality rate in male genitourinary tumors. Hypoxia environment activates the hypoxia‐signalling pathway, principally via hypoxia‐inducible transcription factors (HIF) to activate numerous target genes which mediate embryonic vascularization, metabolism, tumor angiogenesis and the other processes to supply tissues with blood and oxygen. Inflammasomes are multiprotein signal responsible for the maturation of proinflammatory cytokines IL-1β and IL-18 as well as trigger the inflammatory cell pyroptosis. Recent study showed that HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury. However, the role of HIF1α in regulating the progression of bladder cancer has not been examined so far. The present study aimed to investigate the effect of HIF-1α on NLRP3 inflammasome activation in urothelial carcinoma. Methods: In this research, urothelial carcinoma cell lines were treated with NLRP3 inflammasome inducers, LPS/ATP, to induce NLRP3 inflammasome activation. Results: Our preliminary results showed that both T24 and 5637 bladder cancer cells can be induced NLRP3 inflammasome activation and IL-1β secretion. In addition, hypoxia also induces the secretion of IL-1β in T24 cells. We further investigated the effect of NLRP3 inflammasome activation in modulating EMT-related protein levels, migration and invasion in bladder cancer T24 cells. Our results demonstrated that NLRP3 inflammasome activation promotes tumor growth and metastasis in bladder cancer cells. Furthermore, knockdown of HIF1α reduces both inflammatory response and migratory activity in bladder cancer. Conclusions: Collectively, these results suggest that targeting NLRP3 inflammasome might offer potential to treat hypoxic malignant tumor in bladder carcinoma.

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