In the present study, we have tested the effect of dioleoyl phosphatidic acid (PA) on intracellular $Ca_{2+}$ concentration ($[Ca^{2+}]_{i}$) in two human colon cancer cell lines (HCT116 and HT29). PA and lysophosphatidic acid (LPA), a bioactive lysolipid, increased $[Ca^{2+}]_{i}$ in both HCT116 and HT29 cell lines. Increases of $[Ca^{2+}]_{i}$ by PA and LPA were more robust in HCT116 cells than in HT29 cells. A specific inhibitor of phospholipase C (U73122), however, was not inhibitory to the cell responses. Pertussis toxin, a specific inhibitor of $G_{i/o}$ type G proteins, however, had an inhibitory effect on the responses except for an LPA-induced one in HT29 cells. Ruthenium red, an inhibitor of the ryanodine receptor, was not inhibitory on the responses, however, 2-APB, a specific inhibitor of inositol 1,4,5-trisphosphate receptor, completely inhibited both lipid-induced $Ca^{2+}$ increases in both cell types. Furthermore, by using Ki16425 and VPC32183, two structurally dissimilar specific antagonists for $LPA_{1}/LPA_{3}$ receptors, an involvement of endogenous LPA receptors in the $Ca^{2+}$ responses was observed. Ki16425 completely inhibited the responses but the susceptibility to VPC32183 was different to PA and LPA in the two cell types. Expression levels of five LPA receptors in the HCT116 and HT29 cells were also assessed. Our data support the notion that PA could increase $[Ca^{2+}]_{i}$ in human colon cancer cells, probably via endogenous LPA receptors, G proteins and $IP_{3}$ receptors, thereby suggesting a role of PA as an intercellular lipid mediator.
Cluster of differentiation 44 (CD44), a cell surface receptor for hyaluronic acid (HA), is involved in aggressive cancer phenotypes. Herein, we investigated the role of the CD44 standard isoform (CD44s) in hypoxia-inducible $factor-1{\alpha}$ ($HIF-1{\alpha}$) regulation using MCF7 overexpressing CD44s (pCD44s-MCF7). When pCD44s-MCF7 was incubated under hypoxia, levels of $HIF-1{\alpha}$, vascular endothelial growth factor, and the $HIF-1{\alpha}$ response element-derived luciferase activity were significantly increased compared to those in the control MCF7. Incubation of pCD44s-MCF7 cells with HA further increased $HIF-1{\alpha}$ accumulation, and the silencing of CD44s attenuated $HIF-1{\alpha}$ elevation, which verifies the role of CD44s in $HIF-1{\alpha}$ regulation. In addition, the levels of phosphorylated extracellular signal-regulated kinase (ERK) was higher in hypoxic pCD44s-MCF7 cells, and $HIF-1{\alpha}$ accumulation was diminished by the pharmacological inhibitors of ERK. CD44s-mediated $HIF-1{\alpha}$ augmentation resulted in two functional outcomes. First, pCD44s-MCF7 cells showed facilitated cell motility under hypoxia via the upregulation of proteins associated with epithelial-mesenchymal transition, such as SNAIL1 and ZEB1. Second, pCD44s-MCF7 cells exhibited higher levels of glycolytic proteins, such as glucose transporter-1, and produced higher levels of lactate under hypoxa. As a consequence of the enhanced glycolytic adaptation to hypoxia, pCD44s-MCF7 cells exhibited a higher rate of cell survival under hypoxia than that of the control MCF7, and glucose deprivation abolished these differential responses of the two cell lines. Taken together, these results suggest that CD44s activates hypoxia-inducible $HIF-1{\alpha}$ signaling via ERK pathway, and the $CD44s-ERK-HIF-1{\alpha}$ pathway is involved in facilitated cancer cell viability and motility under hypoxic conditions.
Purpose: The significance of neuroendocrine differentiation (NED) in gastric carcinoma (GC) is controversial, leading to ambiguous concepts in traditional classifications. This study aimed to determine the prognostic threshold of meaningful NED in GC and clarify its unclear features in existing classifications. Materials and Methods: Immunohistochemical staining for synaptophysin, chromogranin A, and neural cell adhesion molecule was performed for 945 GC specimens. Survival analysis was performed using the log-rank test and univariate/multivariate models with percentages of NED ($P_{NED}$) and demographic and clinicopathological parameters. Results: In total, 275 (29.1%) cases were immunoreactive to at least 1 neuroendocrine (NE) marker. GC-NED was more common in the upper third of the stomach. $P_{NED}$, and Borrmann's classification and tumor, lymph node, metastasis stages were independent prognostic factors. The cutoff $P_{NED}$ was 10%, beyond which patients had significantly worse outcomes, although the risk did not increase with higher $P_{NED}$. Tumors with ${\geq}10%$ NED tended to manifest as Borrmann type III lesion with mixed/diffuse morphology and poorer histological differentiation; the NE components in this population mainly grew in insulae/nests, which differed from the predominant growth pattern (glandular/acinar) in GC with <10% NED. Conclusions: GC with ${\geq}10%$ NED should be classified as a distinct subtype because of its worse prognosis, and more attention should be paid to the necessity of additional therapeutics for NE components.
Yong Jung Kang;Young Hoon Kwon;Jung Yoon Jang;Jun Ho Lee;Sanggwon Lee;Yujin Park;Hyung Ryong Moon;Hae Young Chung;Nam Deuk Kim
Biomolecules & Therapeutics
/
v.31
no.1
/
pp.73-81
/
2023
Sirtuins (SIRTs) belong to the nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family. They are key regulators of cellular and physiological processes, such as cell survival, senescence, differentiation, DNA damage and stress response, cellular metabolism, and aging. SIRTs also influence carcinogenesis, making them potential targets for anticancer therapeutic strategies. In this study, we investigated the anticancer properties and underlying molecular mechanisms of a novel SIRT1 inhibitor, MHY2251, in human colorectal cancer (CRC) cells. MHY2251 reduced the viability of various human CRC cell lines, especially those with wild-type TP53. MHY2251 inhibited SIRT1 activity and SIRT1/2 protein expression, while promoting p53 acetylation, which is a target of SIRT1 in HCT116 cells. MHY2251 treatment triggered apoptosis in HCT116 cells. It increased the percentage of late apoptotic cells and the sub-G1 fraction (as detected by flow cytometric analysis) and induced DNA fragmentation. In addition, MHY2251 upregulated the expression of FasL and Fas, altered the ratio of Bax/Bcl-2, downregulated the levels of pro-caspase-8, -9, and -3 proteins, and induced subsequent poly(ADP-ribose) polymerase cleavage. The induction of apoptosis by MHY2251 was related to the activation of the caspase cascade, which was significantly attenuated by pre-treatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, MHY2251 stimulated the phosphorylation of c-Jun N-terminal kinase (JNK), and MHY2251-triggered apoptosis was blocked by pre-treatment with SP600125, a JNK inhibitor. This finding indicated the specific involvement of JNK in MHY2251-induced apoptosis. MHY2251 shows considerable potential as a therapeutic agent for targeting human CRC via the inhibition of SIRT1 and activation of JNK/p53 pathway.
Young Hoon Chang;Cheol Min Shin;Hae Dong Lee;Jinbae Park;Jiwoon Jeon;Soo-Jeong Cho;Seung Joo Kang;Jae-Yong Chung;Yu Kyung Jun;Yonghoon Choi;Hyuk Yoon;Young Soo Park;Nayoung Kim;Dong Ho Lee
Journal of Gastric Cancer
/
v.24
no.3
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pp.327-340
/
2024
Purpose: Results of initial endoscopic biopsy of gastric lesions often differ from those of the final pathological diagnosis. We evaluated whether an artificial intelligence-based gastric lesion detection and diagnostic system, ENdoscopy as AI-powered Device Computer Aided Diagnosis for Gastroscopy (ENAD CAD-G), could reduce this discrepancy. Materials and Methods: We retrospectively collected 24,948 endoscopic images of early gastric cancers (EGCs), dysplasia, and benign lesions from 9,892 patients who underwent esophagogastroduodenoscopy between 2011 and 2021. The diagnostic performance of ENAD CAD-G was evaluated using the following real-world datasets: patients referred from community clinics with initial biopsy results of atypia (n=154), participants who underwent endoscopic resection for neoplasms (Internal video set, n=140), and participants who underwent endoscopy for screening or suspicion of gastric neoplasm referred from community clinics (External video set, n=296). Results: ENAD CAD-G classified the referred gastric lesions of atypia into EGC (accuracy, 82.47%; 95% confidence interval [CI], 76.46%-88.47%), dysplasia (88.31%; 83.24%-93.39%), and benign lesions (83.12%; 77.20%-89.03%). In the Internal video set, ENAD CAD-G identified dysplasia and EGC with diagnostic accuracies of 88.57% (95% CI, 83.30%-93.84%) and 91.43% (86.79%-96.07%), respectively, compared with an accuracy of 60.71% (52.62%-68.80%) for the initial biopsy results (P<0.001). In the External video set, ENAD CAD-G classified EGC, dysplasia, and benign lesions with diagnostic accuracies of 87.50% (83.73%-91.27%), 90.54% (87.21%-93.87%), and 88.85% (85.27%-92.44%), respectively. Conclusions: ENAD CAD-G is superior to initial biopsy for the detection and diagnosis of gastric lesions that require endoscopic resection. ENAD CAD-G can assist community endoscopists in identifying gastric lesions that require endoscopic resection.
Park, Jeong-Yeon;Koh, Byum-seok;Kim, Ki-Young;Lee, Dong-Mok;Yoon, Gil-Sang
Design & Manufacturing
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v.15
no.2
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pp.11-16
/
2021
Recently, three-dimensional (3D) cell culture systems, which are superior to conventional two-dimensional (2D) vascular systems that mimic the in vivo environment, are being actively studied to reproduce drug responses and cell differentiation in organisms. Conventional two-dimensional cell culture methods (scaffold-based and non-scaffold-based) have a limited cell growth rate because the culture cannot supply the culture medium as consistently as microvessels. To solve this problem, we would like to propose a 3D culture system with an environment similar to living cells by continuously supplying the culture medium to the bottom of the 3D cell support. The 3D culture system is a structure in which microvascular structures are combined under a scaffold (agar, collagen, etc.) where cells can settle and grow. First, we have manufactured molds for the formation of four types of microvessel-mimicking chips: width / height ①100 ㎛ / 100 ㎛, ②100 ㎛ / 50 ㎛, ③ 150 ㎛ / 100 ㎛, and ④ 200 ㎛ / 100 ㎛. By injection molding, four types of microfluidic chips were made with GPPS (general purpose polystyrene), and a 100㎛-thick PDMS (polydimethylsiloxane) film was attached to the top of each microfluidic chip. As a result of observing the flow of the culture medium in the microchannel, it was confirmed that when the aspect ratio (height/width) of the microchannel is 1.5 or more, the fluid flows from the inlet to the outlet without a backflow phenomenon. In addition, the culture efficiency experiments of colorectal cancer cells (SW490) were performed in a 3D culture system in which PDMS films with different pore diameters (1/25/45 ㎛) were combined on a microfluidic chip. As a result, it was found that the cell growth rate increased up to 1.3 times and the cell death rate decreased by 71% as a result of the 3D culture system having a hole membrane with a diameter of 10 ㎛ or more compared to the conventional commercial. Based on the results of this study, it is possible to expand and build various 3D cell culture systems that can maximize cell culture efficiency by cell type by adjusting the shape of the microchannel, the size of the film hole, and the flow rate of the inlet.
Kim, Iksoo;Kim, Hyeongmin;Ro, Jieun;Jo, Kanghee;Karki, Sandeep;Khadka, Prakash;Yun, Gyiae;Lee, Jaehwi
Biomolecules & Therapeutics
/
v.23
no.3
/
pp.296-300
/
2015
${\beta}$-Lapachone has drawn increasing attention as an anti-inflammatory and anti-cancer drug. However, its oral bioavailability has not been yet assessed, which might be useful to develop efficient dosage forms possibly required for non-clinical and clinical studies and future market. The aim of the present study was thus to investigate pharmacokinetic properties of ${\beta}$-lapachone as well as its first-pass metabolism in the liver, and small and large intestines after oral administration to measure the absolute bioavailability in rats. A sensitive HPLC method was developed to evaluate levels of ${\beta}$-lapachone in plasma and organ homogenates. The drug degradation profiles were examined in plasma to assess the stability of the drug and in liver and intestinal homogenates to evaluate first-pass metabolism. Pharmacokinetic profiles were obtained after oral and intravenous administration of ${\beta}$-lapachone at doses of 40 mg/kg and 1.5 mg/kg, respectively. The measured oral bioavailability of ${\beta}$-lapachone was 15.5%. The considerable degradation of ${\beta}$-lapachone was seen in the organ homogenates but the drug was quite stable in plasma. In conclusion, we suggest that the fairly low oral bioavailability of ${\beta}$-lapachone may be resulted from the first-pass metabolic degradation of ${\beta}$-lapachone in the liver, small and large intestinal tracts and its low aqueous solubility.
Sohn, Yoon Ah;Hwang, Seon A;Lee, Sun Yi;Hwang, In Young;Kim, Sun Whoe;Kim, So Yeon;Moon, Aree;Lee, Yong Soo;Kim, Young Ho;Kang, Keum Jee;Jeong, Choon Sik
Biomolecules & Therapeutics
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v.23
no.1
/
pp.53-59
/
2015
In this study, we investigated the inhibitory activities on gastritis and gastric ulcer using liriodendrin which is a constituent isolated from Kalopanax pictus. To elucidate its abilities to prevent gastric injury, we measured the quantity of prostaglandin $E_2$ ($PGE_2$) as the protective factor, and we assessed inhibition of activities related to excessive gastric acid be notorious for aggressive factor and inhibition of Helicobacter pylori (H. pylori) colonization known as a cause of chronic gastritis, gastric ulcer, and gastric cancer. Liriodendrin exhibited higher $PGE_2$ level than rebamipide used as a positive control group at the dose of $500{\mu}M$. It was also exhibited acid-neutralizing capacity (10.3%) and $H^+/K^+$-ATPase inhibition of 42.6% ($500{\mu}M$). In pylorus-ligated rats, liriodendrin showed lower volume of gastric juice ($4.38{\pm}2.14ml$), slightly higher pH ($1.53{\pm}0.41$), and smaller total acid output ($0.47{\pm}0.3mEq/4hrs$) than the control group. Furthermore liriodendrin inhibited colonization of H. pylori effectively. In vivo test, liriodendrin significantly inhibited both of HCl/EtOH-induced gastritis (46.9 %) and indomethacin-induced gastric ulcer (46.1%). From these results, we suggest that liriodendrin could be utilized for the treatment and/or protection of gastritis and gastric ulcer.
Habib, Abdul Musaweer;Islam, Md. Saiful;Sohel, Md.;Mazumder, Md. Habibul Hasan;Sikder, Mohd. Omar Faruk;Shahik, Shah Md.
Genomics & Informatics
/
v.14
no.4
/
pp.255-264
/
2016
The plethora of genome sequence information of bacteria in recent times has ushered in many novel strategies for antibacterial drug discovery and facilitated medical science to take up the challenge of the increasing resistance of pathogenic bacteria to current antibiotics. In this study, we adopted subtractive genomics approach to analyze the whole genome sequence of the Fusobacterium nucleatum, a human oral pathogen having association with colorectal cancer. Our study divulged 1,499 proteins of F. nucleatum, which have no homolog's in human genome. These proteins were subjected to screening further by using the Database of Essential Genes (DEG) that resulted in the identification of 32 vitally important proteins for the bacterium. Subsequent analysis of the identified pivotal proteins, using the Kyoto Encyclopedia of Genes and Genomes (KEGG) Automated Annotation Server (KAAS) resulted in sorting 3 key enzymes of F. nucleatum that may be good candidates as potential drug targets, since they are unique for the bacterium and absent in humans. In addition, we have demonstrated the three dimensional structure of these three proteins. Finally, determination of ligand binding sites of the 2 key proteins as well as screening for functional inhibitors that best fitted with the ligands sites were conducted to discover effective novel therapeutic compounds against F. nucleatum.
Cisplatin, a platinum-complex, is currently one of the most effective compounds used in the treat-ment of solid tumors. However, its use is limited by severe side effects such as renal toxicity. Our platinum-based drug discovery program is aimed at developing drugs capable of diminishing toxicity and improving selective cytotoxicity. We synthesized new Pt (II) complex analogue containing 1,2-diaminocyclohexane (DACH) as carrier ligand and 1,2-bis (diphenylphosphino) ethane (DPPE) as a leaving group. Furthermore, nitrate was added to improve the solubility. A new series of [Pt(cia-DACH)(DPPE)] . $2NO_3$ (PC) was synthes-ized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), $_{13}$carbon nuclear magnetic resonance (NMR)] .PC demonstrated acceptable and significant antitumor activity against SKOV-3 and OVCAR-3 human ovarian carcinoma cell lines as compared with that of cisplatin. The cytotoxicity of PC in normal cells was found quite less than that of cisplatin using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), ($^3$H)thymidine uptake and glucose consumption tests in rabbit renal proximal tubular cells, human renal cortical cells and tissues. In conclusion, PC is considered to be more selective cytotoxicity toward human ovarian cancer cells than normal human/rabbit kidney cells.
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