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

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 273-273
Author(s):  
H. Williams

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.

2021 ◽  
Vol 22 (23) ◽  
pp. 12756
Author(s):  
Xuan-Mei Piao ◽  
Chaelin You ◽  
Young Joon Byun ◽  
Ho Won Kang ◽  
Junho Noh ◽  
...  

Non-muscle-invasive bladder cancer (NMIBC) is a common disease with a high recurrence rate requiring lifetime surveillance. Although NMIBC is not life-threatening, it can progress to muscle-invasive bladder cancer (MIBC), a lethal form of the disease. The management of the two diseases differs, and patients with MIBC require aggressive treatments such as chemotherapy and radical cystectomy. NMIBC patients at a high risk of progression benefit from early immediate cystectomy. Thus, identifying concordant markers for accurate risk stratification is critical to predict the prognosis of NMIBC. Candidate genetic biomarkers associated with NMIBC prognosis were screened by RNA-sequencing of 24 tissue samples, including 16 NMIBC and eight normal controls, and by microarray analysis (GSE13507). Lastly, we selected and investigated a mitotic checkpoint serine/threonine kinase, BUB1, that regulates chromosome segregation during the cell cycle. BUB1 gene expression was tested in 86 NMIBC samples and 15 controls by real-time qPCR. The performance of BUB1 as a prognostic biomarker for NMIBC was validated in the internal Chungbuk cohort (GSE13507) and the external UROMOL cohort (E-MTAB-4321). BUB1 expression was higher in NMIBC patients than in normal controls (p < 0.05), and the overexpression of BUB1 was correlated with NMIBC progression (log-rank test, p = 0.007). In in vitro analyses, BUB1 promoted the proliferation of bladder cancer cells by accelerating the G2/M transition of the cell cycle. Conclusively, BUB1 modulates the G2/M transition to promote the proliferation of bladder cancer cells, suggesting that it could serve as a prognostic marker in NMIBC.


Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 80
Author(s):  
Roland Kotolloshi ◽  
Martin Hölzer ◽  
Mieczyslaw Gajda ◽  
Marc-Oliver Grimm ◽  
Daniel Steinbach

Bladder cancer is a very heterogeneous disease and the molecular mechanisms of carcinogenesis and progression are insufficiently investigated. From the DNA sequencing analysis of matched non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) samples from eight patients, we identified the tumour-associated gene SLC35F2 to be mutated in the 5′ and 3′ untranslated region (UTR). One mutation in 3′UTR increased the luciferase activity reporter, suggesting its influence on the protein expression of SLC35F2. The mRNA level of SLC35F2 was increased in MIBC compared with NMIBC. Furthermore, in immunohistochemical staining, we observed a strong intensity of SLC35F2 in single tumour cells and in the border cells of solid tumour areas with an atypical accumulation around the nucleus, especially in the MIBC. This suggests that SLC35F2 might be highly expressed in aggressive and invasive tumour cells. Moreover, knockdown of SLC35F2 repressed the growth of bladder cancer cells in the monolayer and spheroid model and suppressed migration and invasion of bladder cancer cells. In conclusion, we suggest that SLC35F2 is involved in bladder cancer progression and might provide a new therapeutic approach, for example, by the anti-cancer drug YM155, a cargo of the SLC35F2 transporter.


2021 ◽  
pp. 1-9
Author(s):  
Emmanuelle Fabiano ◽  
Catherine Durdux ◽  
Bertrand Dufour ◽  
Arnaud Mejean ◽  
Nicolas Thiounn ◽  
...  

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