scholarly journals BGJ398, A Pan-FGFR Inhibitor, Overcomes Paclitaxel Resistance in Urothelial Carcinoma with FGFR1 Overexpression

2018 ◽  
Vol 19 (10) ◽  
pp. 3164 ◽  
Author(s):  
Se Kim ◽  
Haram Ryu ◽  
Chan-Young Ock ◽  
Koung Suh ◽  
Ji Lee ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Single Agent ◽  
D1 Protein ◽  
Growth Factor Receptor ◽  
Mesenchymal Transition ◽  
Effective Strategies ◽  
Cycle Arrest ◽  
Platinum Based Chemotherapy ◽  
Cyclin D1 Protein

Paclitaxel (PTX) is commonly used to treat urothelial carcinoma (UC) after platinum-based chemotherapy has failed. However, single-agent taxane therapy is not sufficient to inhibit tumor progression and drug resistance in advanced UC. Epithelial-to-mesenchymal transition (EMT) induced by fibroblast growth factor receptor (FGFR)1 signaling has been proposed as a mechanism of PTX resistance, but it is unclear whether this can be overcome by FGFR1 inhibition. The present study investigated whether FGFR1 overexpression contributes to PTX resistance and whether FGFR inhibition can enhance PTX efficacy in UC. The effects of PTX combined with the FGFR inhibitor BGJ398 were evaluated in UC cell lines by flow cytometry; Western blot analysis; cell viability, migration, and colony forming assays; and RNA interference. PTX+BGJ398 induced cell cycle arrest and apoptosis in UC cells with mesenchymal characteristics was accompanied by downregulation of cyclin D1 protein and upregulation of gamma-histone 2A family member X and cleaved poly(ADP-ribose) polymerase. Additionally, PTX+BGJ398 synergistically suppressed UC cell migration and colony formation via regulation of EMT-associated factors, while FGFR1 knockdown enhanced the antitumor effect of PTX. These findings provide a basis for development of effective strategies for overcoming PTX resistance in UC through inhibition of FGFR1 signaling.

scholarly journals Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1742
Author(s):  
Melysa Fitriana ◽  
Wei-Lun Hwang ◽  
Pak-Yue Chan ◽  
Tai-Yuan Hsueh ◽  
Tsai-Tsen Liao
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Cancer Stemness ◽  
Mesenchymal Transition

Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.

scholarly journals The Role of Nitric Oxide in Cancer: Master Regulator or NOt?

2020 ◽  
Vol 21 (24) ◽  
pp. 9393
Author(s):  
Faizan H. Khan ◽  
Eoin Dervan ◽  
Dibyangana D. Bhattacharyya ◽  
Jake D. McAuliffe ◽  
Katrina M. Miranda ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Microenvironment ◽  
Master Regulator ◽  
Mesenchymal Transition ◽  
Cycle Arrest

Nitric oxide (NO) is a key player in both the development and suppression of tumourigenesis depending on the source and concentration of NO. In this review, we discuss the mechanisms by which NO induces DNA damage, influences the DNA damage repair response, and subsequently modulates cell cycle arrest. In some circumstances, NO induces cell cycle arrest and apoptosis protecting against tumourigenesis. NO in other scenarios can cause a delay in cell cycle progression, allowing for aberrant DNA repair that promotes the accumulation of mutations and tumour heterogeneity. Within the tumour microenvironment, low to moderate levels of NO derived from tumour and endothelial cells can activate angiogenesis and epithelial-to-mesenchymal transition, promoting an aggressive phenotype. In contrast, high levels of NO derived from inducible nitric oxide synthase (iNOS) expressing M1 and Th1 polarised macrophages and lymphocytes may exert an anti-tumour effect protecting against cancer. It is important to note that the existing evidence on immunomodulation is mainly based on murine iNOS studies which produce higher fluxes of NO than human iNOS. Finally, we discuss different strategies to target NO related pathways therapeutically. Collectively, we present a picture of NO as a master regulator of cancer development and progression.

scholarly journals Bleomycin-enhanced alternative splicing of fibroblast growth factor receptor 2 induces epithelial to mesenchymal transition in lung fibrosis

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Kui-Jun Chen ◽  
Qing Li ◽  
Chang-Mei Weng ◽  
Zhao-Xia Duan ◽  
Dong-Dong Zhang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Lung Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Transgenic Mouse Models ◽  
Mesenchymal Transition

Idiopathic pulmonary fibrosis (IPF) is an important public health problem, and it has few treatment options given its poorly understood etiology; however, epithelial to mesenchymal transition (EMT) of pneumocytes has been implicated as a factor. Herein, we aimed to explore the underlying mechanisms of lung fibrosis mediated by EMT, with a focus on the alternative splicing of fibroblast growth factor receptor 2 (FGFR2), using bleomycin (BLM)-induced lung fibrotic and transgenic mouse models. We employed BLM-induced and surfactant protein C (SPC)-Cre and LacZ double transgenic mouse models. The results showed that EMT occurred during lung fibrosis. BLM inhibited the expression of epithelial splicing regulatory protein 1 (ESRP1), resulting in enhanced alternative splicing of FGFR2 to the mesenchymal isoform IIIc. BLM-induced lung fibrosis was also associated with the activation of TGF-β/Smad signaling. These findings have implications for rationally targetted strategies to therapeutically address IPF.

scholarly journals Honokiol and Magnolol Inhibit Growth, Metastasis and Induce Apoptosis in Human Cholangiocarcinoma

2019 ◽  
Vol 12 (2) ◽  
pp. 759-773
Author(s):  
Worawat Songjang ◽  
Arunya Jiraviriyakul
Keyword(s):  
Cell Lines ◽  
D1 Protein ◽  
Extrinsic Pathway ◽  
Anticancer Properties ◽  
Cycle Arrest ◽  
Low Concentrations ◽  
Cyclin D1 Protein ◽  
High Concentrations ◽  
Magnolia Officinalis ◽  
Biliary Tract Malignancy

Cholangiocarcinoma (CCA) is biliary tract malignancy. Because no specific biomarkers are available, CCA patients frequently present with disseminated tumour that is too late for curative treatment, leading to a high mortality rate. Honokiol and magnolol are the hydroxylated biphenyl compounds isolated from Magnolia officinalis. Many studies have reported that honokiol and magnolol have antitumour effects on various types of cancer, but the evidence of the effects of these compounds on CCA cells has not yet been reported. This study therefore aims to evaluate the antitumour activities of honokiol and magnolol on CCA cell lines. The CCA cell lines were incubated with honokiol and magnolol before determining their responses. The results indicate that low concentrations of honokiol and magnolol suppressed CCA proliferation by induction of cell cycle arrest at G0/G1 and down-regulation of cyclin D1 protein. Moreover, these compounds exhibited an antimetastasis ability mediated by inhibiting migration, adhesion, and the MMP activities of CCA cells. In addition, at high concentrations of honokiol and magnolol activated CCA cell death associated with the apoptosis signalling pathway, along either an intrinsic or extrinsic pathway. Our data provides evidence that honokiol and magnolol have potential anticancer properties and are promising compounds for alternative CCA treatment.

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