28 research outputs found
Long-term depletion of Cereblon induces mitochondrial dysfunction in cancer cells
No full textCereblon (CRBN) is a multi-functional protein that acts as a substrate receptor of the E3 ligase complex and a molecular chaperone. While CRBN is proposed to function in mitochondria, its specific roles are yet to be established. Here, we showed that knockdown of CRBN triggers oxidative stress and calcium overload in mitochondria, leading to disruption of mitochondrial membrane potential. Notably, long-term CRBN depletion using PROteolysis TArgeting Chimera (PROTAC) induced irreversible mitochondrial dysfunction, resulting in cell death. Our collective findings indicate that CRBN is required for mitochondrial homeostasis in cells.
Licochalcone A inhibits hypoxia-inducible factor-1α accumulation by suppressing mitochondrial respiration in hypoxic cancer cells
No full textHypoxia-inducible factor (HIF)-1 is an important regulator of the cellular response in the hypoxic tumor environment. While searching for HIF inhibitors derived from natural products that act as anticancer agents, we found that Glycyrrhiza uralensis exerts HIF-1 inhibitory activity in hypoxic cancer cells. Among the five components of G. uralensis, licochalcone A was found to potently suppress hypoxia-induced HIF-1α accumulation and expression of HIF-1α target genes, including GLUT1 and PDK1 in HCT116 cells. Licochalcone A also enhances intracellular oxygen content by directly inhibiting mitochondrial respiration, resulting in oxygen-dependent HIF-1α degradation. Hence, licochalcone A may effectively inhibit ATP production, primarily by reducing the mitochondrial respiration-mediated ATP production rate rather than the glycolysis-mediated ATP production rate. This effect subsequently suppresses cancer cell viability, including that of HCT116, H1299, and H322 cells. Consequently, these results suggest that licochalcone A has therapeutic potential in hypoxic cancer cells.
Recent Advances in Pathology
No full textAuthor Institution: Department of Pathology, The Ohio State Universit
Publisher Correction: Inflammation induces two types of inflammatory dendritic cells in inflamed lymph nodes
No full textThe original version of this article unfortunately contained an error in the author name Dongchan Yang, which was incorrectly given as Dongchan Yang Sung.</jats:p
Abstract 4803: Epigenome signatures during gastric carcinogenesis detected by MBD-seq and RRBS technologies
No full textAlteration of the epigenome during carcinogenesis of intestinal-type gastric cancer.
No full text 34 Background: Next-generation sequencing (NGS) is opening a new era for understanding how the human genome is altered in the process of cancer development. We sought to establish an epigenome map based on the DNA methylome during gastric carcinogenesis, paving the way to a better understanding of the origins of gastric cancer using NGS-based epigenome analysis. Methods: We purified DNA in laser-capture microdissected (LCM) cells of normal mucosa, intestinal metaplasia (IM), and gastric cancer from frozen samples of one patient with intestinal type gastric tumor. Two NGS-based epigenome analyses were performed on each DNA: ‘MBD-seq’ (methylated DNA binding domain sequencing) and ‘RRBS’ (reduced representation bisulfite sequencing). Results: MBD-seq and RRBS generated ~25.7 million and ~15.1 million reads respectively, per lane on average. The sequence data matched with 79% (21,514/27,191) and 55% (14,991/27,191) of promoter sequences from UCSC genome browser, respectively. We then identified about one thousand differentially methylated promoters (DMPs), which were altered in IM and in gastric cancer or in gastric cancer compared to that of gastric mucosa. In particular, hypomethylation was detected in 30 promoters by MBD-seq and 173 by RRBS, indicating that RRBS is highly informative for identifying hypomethylated DMPs associated with gene activation during carcinogenesis. Conclusions: We identified several novel hyper- or hypomethylated biomarkers for IM or gastric cancer using NGS-based epigenome analysis. Our reference epigenome map may provide a foundation for future studies exploring the prognostic or preventive biomarker for early stage of gastric cancer. </jats:p
Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to ALK inhibitors in lung cancer
No full textAnaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta‐analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi‐resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi‐resistant cells, and further interpreted its impact on the resistant signatures through drug‐induced RNA‐sequencing data. Our transcriptome‐guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy
Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma
No full textBackground: Although programmed death-1 (PD-1) blockade is effective in treating several types of cancer, the efficacy of this agent in glioblastoma (GBM) is largely unknown. Methods: We evaluated therapeutic effects of anti-PD-1, temozolomide (TMZ), and their combination in an orthotopic murine GBM model. The phenotype, number, and composition of lymphocytes were evaluated using flow cytometry. Transcriptional profiles of tumor tissues were analyzed using microarrays. Generation of antitumor immunological memory was investigated upon rechallenge. Results: Combined treatment with anti-PD-1 and TMZ yielded synergistic antitumor efficacy in the presence of donor-originated PD-1+CD8+ T cells in vitro, necessitating in vivo validation. Whereas TMZ did not rescue GBM-implanted mice, anti-PD-1 completely eradicated GBM in 44.4% of mice, and combination of anti-PD-1 and TMZ in all mice. Anti-PD-1 significantly increased the number of tumor-infiltrating lymhpocytes (TILs), and reduced frequencies of exhausted T cells and regulatory T cells. However, combining TMZ with anti-PD-1 significantly decreased the number of TILs, which was also observed with TMZ treatment alone. A transcriptome analysis of tumor tissues revealed that anti-PD-1 monotherapy perturbed immune-related genes, distinctly with combined therapy. Upon rechallenge, tumor growth was not observed in mice cured by anti-PD-1 monotherapy, whereas tumors regrew in the combination group. Furthermore, an analysis of peripheral blood revealed that antitumor memory T cells were generated in mice cured by anti-PD-1 monotherapy, not in the combination group. Conclusion: PD-1 blockade induces long-term therapeutic response, and combination with TMZ further enhances antitumor efficacy. However, immunological memory is provoked by anti-PD-1 monotherapy, not by combined therapy.restrictio
Spermidine Promotes Human Hair Growth and Is a Novel Modulator of Human Epithelial Stem Cell Functions
No full textThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Methylation of the CDX2 promoter in H. pylori-infected gastric mucosa increases with age and its rapid demethylation in gastric tumors is associated with upregulated gene expression
No full textPathological changes in the epigenetic landscape of chromatin are hallmarks of cancer. The caudal-type homeobox gene CDX2 is not expressed in normal gastric epithelia but rather in adult intestinal epithelia, and it is overexpressed in intestinal metaplasia (IM). However, it remains unclear how CDX2 transcription is suppressed in normal gastric epithelial cells and overexpressed in IM. Here, we demonstrate that methylation of the CDX2 promoter increases with age in Helicobacter pylori-positive, noncancerous gastric tissue, whereas the promoter is demethylated in paired gastric tumors in which CDX2 is upregulated. Moreover, we also found that the CDX2 promoter is demethylated in IM as well as gastric tumor. Immunohistochemistry revealed that CDX2 is present in foci of parts of the gastric mucosae but highly expressed in IM as well as in gastric tumors, suggesting that the elevated level of CDX2 in IM and gastric tumors may be attributable to promoter demethylation. Our data suggest that CDX2 repression may be associated with promoter methylation in noncancerous H. pylori-positive mucosa but its upregulation might be attributable to increased promoter activity mediated by chromatin remodeling during gastric carcinogenesis.
