Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice

Bladder cancer is among the top ten most common cancers, with about ~380,000 new cases and ~150,000 deaths per year worldwide. Tumor relapse following chemotherapy treatment has long been a significant challenge towards completely curing cancer. We have utilized a patient-derived bladder cancer xenograft (PDX) platform to characterize molecular mechanisms that contribute to relapse following drug treatment in advanced bladder cancer. Transcriptomic profiling of bladder cancer xenograft tumors by RNA-sequencing analysis, before and after relapse, following a 21-day cisplatin/gemcitabine drug treatment regimen identified methionine adenosyltransferase 1a (MAT1A) as one of the significantly upregulated genes following drug treatment. Survey of patient tumor sections confirmed elevated levels of MAT1A in individuals who received chemotherapy. Overexpression of MAT1A in 5637 bladder cancer cells increased tolerance to gemcitabine and stalled cell proliferation rates, suggesting MAT1A upregulation as a potential mechanism by which bladder cancer cells persist in a quiescent state to evade chemotherapy.

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Inhibition of growth, migration and invasion of human bladder cancer cells by antrocin, a sesquiterpene lactone isolated from Antrodia cinnamomea, and its molecular mechanisms

Cancer Letters ◽

10.1016/j.canlet.2015.11.046 ◽

2016 ◽

Vol 373 (2) ◽

pp. 174-184 ◽

Cited By ~ 32

Author(s):

Kun-Yuan Chiu ◽

Chun-Chi Wu ◽

Chi-Hao Chia ◽

Shih-Lan Hsu ◽

Yew-Min Tzeng

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Sesquiterpene Lactone ◽

Molecular Mechanisms ◽

Migration And Invasion ◽

Human Bladder Cancer ◽

Human Bladder ◽

Inhibition Of Growth ◽

Bladder Cancer Cells ◽

Human Bladder Cancer Cells

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SLC35F2, a Transporter Sporadically Mutated in the Untranslated Region, Promotes Growth, Migration, and Invasion of Bladder Cancer Cells

Cells ◽

10.3390/cells10010080 ◽

2021 ◽

Vol 10 (1) ◽

pp. 80

Author(s):

Roland Kotolloshi ◽

Martin Hölzer ◽

Mieczyslaw Gajda ◽

Marc-Oliver Grimm ◽

Daniel Steinbach

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Untranslated Region ◽

Tumour Cells ◽

Invasive Bladder Cancer ◽

Migration And Invasion ◽

Sequencing Analysis ◽

Muscle Invasive Bladder Cancer ◽

Bladder Cancer Cells ◽

Muscle Invasive

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.

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Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells

Cell Death and Disease ◽

10.1038/s41419-021-04306-2 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Yadong Sun ◽

Niklas Berleth ◽

Wenxian Wu ◽

David Schlütermann ◽

Jana Deitersen ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Death ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Mtor Inhibitors ◽

Mtor Inhibition ◽

Combined Application ◽

Regulated Cell Death ◽

Bladder Cancer Cells ◽

Dependent Cell

AbstractFerroptosis is a form of regulated cell death that emerges to be relevant for therapy-resistant and dedifferentiating cancers. Although several lines of evidence suggest that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms remain unclear. Fin56, a type 3 ferroptosis inducer, triggers ferroptosis by promoting glutathione peroxidase 4 (GPX4) protein degradation via a not fully understood pathway. Here, we determined that Fin56 induces ferroptosis and autophagy in bladder cancer cells and that Fin56-triggered ferroptosis mechanistically depends on the autophagic machinery. Furthermore, we found that autophagy inhibition at different stages attenuates Fin56-induced oxidative stress and GPX4 degradation. Moreover, we investigated the effects of Fin56 in combination with Torin 2, a potent mTOR inhibitor used to activate autophagy, on cell viability. We found that Fin56 synergizes with Torin 2 in cytotoxicity against bladder cancer cells. Collectively, our findings not only support the concept that ferroptosis is a type of autophagy-dependent cell death but imply that the combined application of ferroptosis inducers and mTOR inhibitors is a promising approach to improve therapeutic options in the treatment of bladder cancer.

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SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1467-6 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 4

Author(s):

Haiyang Yu ◽

Chun-Li Wu ◽

Xiangyu Wang ◽

Qianhong Ban ◽

Chunhua Quan ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Death ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Combined Treatment ◽

New Drugs ◽

Tumor Inhibition ◽

Bladder Cancer Cells ◽

Jaspine B

Abstract Background A natural compound Jaspine B and its derivative possess potential anti-cancer activities; However, little is known about the underlying mechanism. Here, the role of a new autophagy inducer Jaspine B derivative C-2 in suppressing bladder cancer cells was researched in vitro and in vivo. Methods The underlying mechanisms and anticancer effect of C-2 in bladder cancer cells were investigated by MTT, western blotting, immunoprecipitation and immunofluorescence assays. The key signaling components were investigated by using pharmacological inhibitors or specific siRNAs. In vivo, we designed a C-2 and SP600125 combination experiment to verify the effectiveness of compound. Results C-2 exhibits cytotoxic effect on bladder cancer cells, and JNK activated by C-2 triggers autophagy and up-regulates SQSTM1/p62 proteins, contributing to activation of Nrf2 pathway. Utilization of JNK inhibitor SP600125 or knockdown of JNK by siRNA potentiate the cytotoxicity of C-2 through down-regulation of p62 and LC3II proteins and up-regulation of active-Caspase3 proteins, enhance the cell death effect, facilitating the switch from autophagy to apoptosis. In vivo study, C-2 suppresses tumor growth in a xenograft mouse model of EJ cells without observed toxicity. Combined treatment with SP600125 further enhances tumor inhibition of C-2 associated with enhanced activation of caspase3 and reduction of autophagy. Conclusions It reveals a series of molecular mechanisms about SP600125 potentiate the cytotoxicity and tumor inhibition of C-2 in bladder cancer cells through promoting C-2-induced apoptosis, expecting it provides research basis and theoretical support for new drugs development.

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Overexpressed circ-CEP128, a potential new circular RNA biomarker, promotes cisplatin resistance of bladder cancer cells by regulating necroptosis

10.21203/rs.3.rs-44293/v1 ◽

2020 ◽

Author(s):

Ming Sun ◽

Wenyan Zhao ◽

Bin Zhang ◽

Donghua Geng ◽

Shuqiang Li ◽

...

Keyword(s):

Drug Resistance ◽

Bladder Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Cisplatin Resistance ◽

Expression Level ◽

Cancer Tissue ◽

Diagnostic Biomarker ◽

Bladder Cancer Cells

Abstract Background Bladder cancer (BC) is the most common malignancy of urinary system and cisplatin (DDP) remains the only chemotherapy option for treatment of BC at the advanced stage. The critical molecules involved in the regulation of cisplatin resistance are still largely unknown. CircRNAs has been demonstrated to be involved in tumorigenesis and development and drug resistance of various cancer cells. CircCEP128 contributed to BC progression by regulating miR-145-5p/MYD88/MAKP axis. However, functions and molecular mechanisms of circCEP128 in DDP resistance of bladder cancer cells still remain largely unclear. Methods Bladder cancer tissue and the corresponding adjacent normal tissue as well as serum samples were obtained from a total of 60 BC patients who received the same cisplatin-based chemotherapy. The expression level of circCEP128 in tissues and serums was measured using qRT-PCR. WB was utilized to detect expression level of PCNA, Cyclin D1, RIPK3, p-RIPK3, MLKL or p-MLKL. Functionally, BC cell viability and proliferation are measured through relevant experiments, including CCK8 assay and cell colony formation assay. Results In the current study, we demonstrated that circCEP128 expression was distinctly elevated in the BC tissues and serums, especially in the chemoresistant BC tissues or cell lines, correlated with poor prognosis of BC patients. In addition, ROC curve suggested that circCEP128 might serve as an effective diagnostic biomarker for BC and treatment. Furthermore, cell function assays showed that circCEP128 silencing by siRNA could reverse the drug-resistance of BC cells to cisplatin by inducing necroptosis through regulation of RIPK3/MLKL signaling pathway. Conclusions Our findings indicated that circCEP128 may serve as a valuable diagnostic biomarker in BC and contribute to cisplatin resistance of bladder cancer cells by repressing necroptosis through RIPK3/MLKL signaling pathway. These findings provide novel insights into the role of circCEP128 as a biomarker for the diagnosis and treatment target of BC.

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