Adapting and Surviving: Intra and Extra-Cellular Remodeling in Drug-Resistant Gastric Cancer Cells

Russi, Sabino; Verma, Henu Kumar; Laurino, Simona; Mazzone, P.; Storto, Giovanni; Nardelli, Anna; Zoppoli, Pietro; Calice, Giovanni; Rocca, Francesco La; Sgambato, Alessandro; Lucci, Valeria; Falco, Geppino; Ruggieri, Vitalba

doi:10.3390/ijms20153736

Cited by 47 publications

(33 citation statements)

References 154 publications

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“…An important clinical readout of the CSC phenotype is the increased drug resistance, namely to 5-FU in GC, which in patients might be related with the worse prognosis, already described [64,65]. We confirmed that SORE6+ cells have increased resistance to apoptosis and screened genes that could be involved in this process.…”

Section: Discussionsupporting

confidence: 74%

A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin

Pádua

Barros

Amaral

et al. 2020

Cancers

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Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6– cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs.

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Section: Discussionsupporting

confidence: 74%

A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin

Pádua

Barros

Amaral

et al. 2020

Cancers

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“…Apoptosis, or programmed cell death, is critical for the success of chemotherapies against various cancers and cancer cell resistance [32]. Failure in gastric cancer therapy may be the result of defective apoptosis process accompanied with the underlying mechanisms of Bcl-2 protein overexpression, hypoxia, and tumor microenvironment remodeling [33,34]. Nowadays, gastric cancer cells are acquiring resistance to TRAIL and various chemotherapy approaches have been investigated to increase TRAIL sensitivity in gastric cancer cells [35,36].…”

Section: Discussionmentioning

confidence: 99%

Benzyl Isothiocyanate Induces Apoptosis via Reactive Oxygen Species-Initiated Mitochondrial Dysfunction and DR4 and DR5 Death Receptor Activation in Gastric Adenocarcinoma Cells

Han

Sohn

et al. 2019

Biomolecules

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Benzyl isothiocyanate (BITC) is known to inhibit the metastasis of gastric cancer cells but further studies are needed to confirm its chemotherapeutic potential against gastric cancer. In this study, we observed cell shrinkage and morphological changes in one of the gastric adenocarcinoma cell lines, the AGS cells, after BITC treatment. We performed 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, a cell viability assay, and found that BITC decreased AGS cell viability. Reactive oxygen species (ROS) analyses using 2′,7′-dichlorofluorescin diacetate (DCFDA) revealed that BITC-induced cell death involved intracellular ROS production, which resulted in mitochondrial dysfunction. Additionally, cell viability was partially restored when BITC-treated AGS cells were preincubated with glutathione (GSH). Western blotting indicated that BITC regulated the expressions of the mitochondria-mediated apoptosis signaling molecules, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and cytochrome c (Cyt c). In addition, BITC increased death receptor DR5 expression, and activated the cysteine-aspartic proteases (caspases) cascade. Overall, our results showed that BITC triggers apoptosis in AGS cells via the apoptotic pathways involved in ROS-promoted mitochondrial dysfunction and death receptor activation.

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“…5 Traditional chemotherapy drugs for GC have more side effects, and the technology of targeted therapy is still immature. 6 Hence, to explore the targeted therapy of GC development is the key to find a new therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

<p>USP8 Inhibitor Suppresses HER-2 Positive Gastric Cancer Cell Proliferation and Metastasis via the PI3K/AKT Signaling Pathway</p>

Sun

Shen

Zheng

et al. 2020

OTT

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Referring to global cancer statistics, the incidence of gastric cancer (GC) was ranked sixth; however, detailed mechanisms underlying its development were not thoroughly investigated. Previous studies have reported that inhibition of ubiquitin-specific peptidase 8 (USP8) induced degradation of several receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), embryonic stem cells (ESCs), etc. Nevertheless, the regulation of HER-2 by USP8 and the molecular mechanisms controlling their role in the pathogenesis of GC remain unknown. Patients and Methods: A total of 69 patients with histologically confirmed GC were recruited to satisfy the purpose of this study. Initially, tumor samples and GC cell lines were used to detect USP8 and HER-2 levels. Next, MTT and colony formation assays were applied to analyze cell proliferation capability. Cell migration and invasion ability were examined by transwell assays. To examine related mRNA and protein expressions, Western blot assays and quantitative real-time PCR (qRT-PCR) were performed. Immunofluorescence was used to detect the effect of USP8 inhibitor on GC cells. Finally, in vivo experiments were used to examine the effect of USP8 inhibitor. Results: Patients with USP8 high-expression tumors have shown worse overall survival while opposite results found in patients with low USP8 expressions. Regarding disease prognosis, patients with low expression of USP8 and HER-2 were performed better prognosis, whereas those with overexpression of USP8 and HER-2 shown poor prognosis. USP8 inhibitor significantly inhibited HER-2 positive cell NCI-N87 proliferation and metastasis. In addition, USP8 stabilizes HER-2, preventing it from ubiquitin proteasome-mediated degradation. In vivo studies confirmed that the USP8 inhibitor inhibited HER-2 positive cell NCI-N87 tumor growth. However, it did not affect the HER2-negative cell MGC-803. Careful investigation unraveled that the USP8 inhibitor significantly inhibited NCI-N87 cell proliferation and metastasis via phosphatidylinositol-3-kinases/protein-serine-threonine kinase (PI3K/AKT) pathway. Conclusion: The USP8 inhibited HER-2 positive GC cell proliferation and migration in vivo and in vitro and probably served as a novel potential therapeutic biomarker for HER-2 positive GC.

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Adapting and Surviving: Intra and Extra-Cellular Remodeling in Drug-Resistant Gastric Cancer Cells

Cited by 47 publications

References 154 publications

A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin

A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin

Benzyl Isothiocyanate Induces Apoptosis via Reactive Oxygen Species-Initiated Mitochondrial Dysfunction and DR4 and DR5 Death Receptor Activation in Gastric Adenocarcinoma Cells

<p>USP8 Inhibitor Suppresses HER-2 Positive Gastric Cancer Cell Proliferation and Metastasis via the PI3K/AKT Signaling Pathway</p>

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