Biology subjects

Inoko, A.

Publications and source records attributed to Inoko, A..

6 recordsLinked to original sources

bioRxiv2024

Chemotherapy resistance due to epithelial-to-mesenchymal transition is caused by abnormal lipid metabolic balance

Invasive cancer is defined by the loss of epithelial cell traits resulting from the ectopic expression of epithelial-mesenchymal transition (EMT)-related transcription factors such as Snail. Although EMT is known to impart chemoresistance to cancer cells, the precise molecular mechanisms remain elusive. We found that Snail expression confers chemoresistance by upregulating the cholesterol efflux pump ABCA1 as a countermeasure to the excess of cytotoxic free cholesterol relative to its major interaction partner in cellular membranes, sphingomyelin. This imbalance is introduced by the transcriptional repression of enzymes involved in the biosynthesis of sphingomyelin by Snail. Inhibiting esterification of cholesterol, which renders it inert, selectively suppresses growth of a xenograft model of Snail-positive kidney cancer. Our findings offer a new perspective on lipid-targeting strategies for invasive cancer therapy.

cell biology↗

bioRxiv2024

Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an uncommon yet deadly cancer linked to asbestos exposure. The lack of effective early diagnosis and treatment leads to reduced life expectancy among patients with MPM. This study is aimed to identify a novel molecular target inhibitor to develop more effective therapeutics for MPM. Our drug screening assay showed that the fatty acid synthase (FASN) inhibitor cerulenin demonstrates strong and selective anti-proliferative properties against NF2/CDKN2A(p16)-deficient MPM cells, surpassing the effects of cisplatin or pemetrexed. FASN protein is frequently detected in NF2/p16-deficient MPM tumor-derived tissues (15/15, 100%), but rarely in NF2/p16-intact MPM tumors (8/25, 32%). Notably, cerulenin administration successfully reduced the growth of NF2/p16-deficient MPM tumors in xenografted mice. Cerulenin inhibits mitochondrial fission by targeting dynamin-related protein 1 (DRP1) in NF2/p16-deficient cells. Moreover, the disruption of the FASN gene leads to increased ubiquitination of DRP1. These findings suggest that FASN might play a role in the tumorigenesis of MPM cells through the regulation of mitochondrial dynamics. This research offers a novel perspective on the potential development of precision medicine for MPM.

cancer biology↗

bioRxiv2024

Coherent Raman microscopy detects nucleolar defects through amide I peak shifts originating from b-sheets: an application to visualizing ongoing cellular senescence

Cellular senescence occurs through the accumulation of many kinds of stresses. Senescent cells in tissues also cause various age-related disorders. Therefore, detecting them without labeling is beneficial. However, existing biomarkers have limitations of requiring fixation and labeling, or their molecular backgrounds are uncertain. Coherent anti-Stokes Raman scattering (CARS) spectroscopic imaging is a novel option because it can assess and visualize molecular structures based on their molecular fingerprint. Here, we present a new label-free method to visualize cellular senescence by obtaining molecular fingerprint signals in nucleoli using a CARS microspectroscopic system. We found the peak of the nucleolar amide I band shifted to a higher wavenumber in binuclear senescent cells, which reflects changes in the protein secondary structure from predominant -helices to {beta}-sheets originating from amyloid-like aggregates. Following this, we developed a procedure that can visualize the senescent cells by providing the ratios and subtractions of these two components. We also confirmed that the procedure can visualize nucleolar aggregates due to unfolded/misfolded proteins produced by proteasome inhibition. Finally, we found that this method can help visualize the nucleolar defects in naive cells even before binucleation. Thus, our method is beneficial to evaluate ongoing cellular senescence through label-free imaging of nucleolar defects.

cell biology↗

bioRxiv2024

Label-free visualization of ciliary rootlets in mouse brain

Neuronal primary cilia are important role in brain development, sensory perception and neurogenesis. Rootletin, a fibrous protein composed of coiled-coil motifs, is a major structural component of ciliary rootlets and is essential for understanding ciliary functions. However, the precise mechanisms by which Rootletin influences ciliary dynamics and impacts neuronal function remain largely unknown, primarily due to the challenges in visualizing these structures. Here, we describe a label-free, rapid, and highly sensitive method to visualize Rootletin molecules in brain tissue. This platform integrates a second harmonic generation (SHG) microscope and background reduction by a one-step chemical pretreatment. Additionally, we employ coherent anti-Stokes Raman scattering imaging to simultaneously determine the cellular regions and intracellular locations of SHG signals. By applying this multimodal multiphoton imaging to mouse hippocampus, we found that neuronal ciliary rootlets were found to exhibit highly organized specific intracellular distributions. Moreover, the formation of ciliary rootlets precedes that of primary cilia. These findings highlight the utility of our label-free imaging platform in developmental and neuroscience research, providing a new tool to characterize ciliary dynamics and neuronal function.

biophysics↗

bioRxiv2024

The yolk sac vasculature in early avian embryo provides a novel model for the analysis of cancer extravasation

Hematogenous metastasis, a key trait of cancer cells, involves a complex sequence of cell migration steps, including intravasation, circulation, arrest in capillary vessels, and extravasation. Among these steps, extravasation is challenging to image in amniotes like humans and mice due to its unpredictable timing and location, limiting our understanding of cellular and molecular mechanisms through imaging. Establishing a new cancer carrier model with high-resolution imaging capabilities in amniotes is crucial. In this study, we investigated the yolk sac vasculature (YSV) of early avian embryos (chickens and quail) as a new model for studying extravasation, offering excellent imaging capabilities. We examined the YSV structure and attempted fluorescent labeling to enhance visibility. We then injected mCherry-labeled HT-1080 cells into YSV and observed their behavior, revealing distinct morphologies and extravasation dynamics. Our findings suggest that the YSV model holds promise as a novel cancer carrier model for elucidating cellular and molecular mechanisms through imaging-based approaches.

cancer biology↗

bioRxiv2018

Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population

The etiology of pancreatic cancer remains largely unknown. Here, we report the results of a meta-analysis of three genome-wide association studies (GWASs) comprising 2,039 pancreatic cancer cases and 32,592 controls, the largest sample size in the Japanese population. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P<5.0x10-8) and 4 suggestive loci (P<1.0x10-6) for pancreatic cancer. Of these risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (odds ratio (OR)=1.46, 95% CI=1.29-1.66, P=4.28x10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant predicted to be highly deleterious. Additionally, the gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified GP2 gene variants were pleiotropic for multiple traits, including type 2 diabetes, hemoglobin A1c (HbA1c) levels, and pancreatic cancer. Mendelian randomization analyses corroborated causality between HbA1c and pancreatic cancer. These findings suggest that GP2 gene variants are associated with pancreatic cancer susceptibility in the Japanese population, prompting further functional characterization of this locus.

genetics↗