Apoptotic and Non-apoptotic Programmed Cell Death in Pathophysiology

Song-Iy Han · Sung-Chul Lim 조선대학교 의학연구원 2006 The Medical Journal of Chosun University Vol.31 No.2

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Role of apoptotic and necrotic cell death under physiologic conditions (Mini Review)

Song Iy Han,Yong Seok Kim,Tae Hyoung Kim 한국생화학분자생물학회 2008 BMB Reports Vol.41 No.1

HEAT SHOCK-INDUCED ACTIC POLYMERIZATION, SAPK/JNK ACTIVATION, AND HEAT-SHOCK PROTEIN EXPRESSION ARE MEDIATED BY GENISTEIN-SENSITIVE TYROSINE KINASE(S) IN K562 CELLS

HAN, SONG IY,HA, KWON-SOO,KANG, KWANG IL,KIM, HAN DO,KANG HO SUNG 부산대학교 유전공학연구소 2000 분자생물학 연구보 Vol.16 No.-

Upon exposure to elevated growth temperatures, mammalian cells exhibit a variety of cellular responses, such as the expression of heat-shock proteins (HSPs) and the activation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). In this study, we show that heat shock transiently induces morphological change (cell elongation) and polymerization of actin, but not of microtubules, in human erythroleukaemic K562 cells. Pretreatment with actinomycin D or cycloheximede did not prevent the heat shock-induced cell elongation and actin reorganization, indicating that gene transcription and protein synthesis are not required for this phenomenon. The alterations in cell morphology and actin struture in response to heat shock were specifically inhibited by genistein, a tyrosine kinase inhibitor, but not by other kinase inhibitors, including tyrosine kinase inhibitors(herbimycin and tyrphostin) and protein kinase C inhibitors (staurosporin and H7). The activities of genistein-sensitive tyrosine kinase (GTK) and c-Src were enhanced by heat-shock treatment. In addition, a 75 kDa protein was highly phosphorylated in its tyrosine residues(s) by heat shock, and the phosphorylation was highly phosphorylated in its tyrosine residues(s) by heat shock, and the phosphorylation was prevented by genistein pretreatment. Genistein also inhibited the heat-shock- induced SAPK/JNK activation and HSP expression. In contrast, while colchicine, a microtubule-disrupting agent, was able to induce actin polymerization and SAPK/JNK activation, these events were not inhibited by genistein. These results suggest that the heat-shock-induced actin polymerzation. HSP expression, and SAPK/JNK activation may be mediated by the specific signal pathway involving GTK(s), while colchicine-induced actin polymerization and SAPK/JNK activation is regulated in a different manner.

Nicotine Acid의 血淸脂質에 미치는 效果 : IV. Effects of Nicotinic Acid on Serum Lipids

宋世燁,金淑伊,金容復,李章圭 中央醫學社 1941 中央醫學 Vol.10 No.5

Nicotinic acid in a dose of 3 grams daily was given to 18 hyperlipemic patients having essential hypertension or obesity for a period of 12 weeks in order to evaluate its effects on serum lipids. Following were the results. 1. The administration of nicotinic acid had to be interrupted within 1 week in 7 out of 18 patients due to the side effects like cutaneous flushing, itching, nausea, vomiting and diarrhea. 2. The side effects of nicotinic acid appeared to be more severe in Koreans than in the cases reported in the foreign literatures. 3. Of all the serum lipids components, β-lipoprotein cholesterol decreased the most after the administration of nicotinic acid, and therefore, the ratio of β/? lipoprotein cholesterol. Serum phospholipids tended to decrease but to the extent of statistical insignificance. 4. Nicotinic acid, despite of its frequent side effects, appears to be an useful anti-cholesterol agent as it selectively decreases β-lipoprotein cholesterol which has the closest relationships with atherosclerosis.

Extracellular acidity enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via DR5 in gastric cancer cells

Ran Hong,Song Iy Han 대한약리학회 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.5

The tumor microenvironment greatly influences cancer cell characteristics, and acidic extracellular pH has been implicated as an essential factor in tumor malignancy and the induction of drug resistance. Here, we examined the characteristics of gastric carcinoma (GC) cells under conditions of extracellular acidity and attempted to identify a means of enhancing treatment efficacy. Acidic conditions caused several changes in GC cells adversely affecting chemotherapeutic treatment. Extracellular acidity did inhibit GC cell growth by inducing cell cycle arrest, but did not induce cell death at pH values down to 6.2, which was consistent with downregulated cyclin D1 and up-regulated p21 mRNA expression. Additionally, an acidic environment altered the expression of atg5, HSPA1B, collagen XIII , collagen XXAI , slug, snail , and zeb1 genes which are related to regulation of cell resistance to cytotoxicity and malignancy, and as expected, resulted in increased resistance of cells to multiple chemotherapeutic drugs including etoposide, doxorubicin, daunorubicin, cisplatin, oxaliplatin and 5-FU. Interestingly, however, acidic environment dramatically sensitized GC cells to apoptosis induced by tumor necrosis factor-related apoptosisinducing ligand (TRAIL). Consistently, the acidity at pH 6.5 increased mRNA levels of DR4 and DR5 genes, and also elevated protein expression of both death receptors as detected by immunoblotting. Gene silencing analysis showed that of these two receptors, the major role in this effect was played by DR5. Therefore, these results suggest that extracellular acidity can sensitize TRAIL-mediated apoptosis at least partially via DR5 in GCs while it confers resistance to various type of chemotherapeutic drugs.

Interpretation of Pin-1 and VEGF-C expression in breast infiltrating duct carcinoma

Kim, Byung-Chul,Han, Song-Iy,Lim, Sung-Chul Spandidos Publications 2009 Oncology reports Vol.22 No.6

<P>Pin-1 has been shown to regulate several phases of the cell cycle and is strikingly overexpressed in many human cancers. Vascular endothelial growth factor (VEGF)-C is a potent lymphangiogenic factor produced by tumor and stromal cells. However, little is known about the roles of Pin-1 and VEGF-C in breast carcinoma. p53 protein and cyclin D1 overexpressions have been shown to play a role as prognostic factors in many human cancers. To better understand the roles of Pin-1 and VEGF-C in breast carcinoma, we evaluated the immunohistochemical expression of Pin-1 and VEGF-C in relationship with p53 protein or cyclin D1 overexpression and clinicopathological parameters in 128 mammary infiltrating duct carcinomas. There was a positive expression in 100% of Pin-1, 88% of VEGF-C, 35% of p53 protein, and 66% of cyclin D1 in the breast carcinoma. Correlation of the positive expression of Pin-1 with tumor grade (p<0.01) and lymph node metastasis or cyclin D1 overexpression (p<0.05, respectively) was statistically significant. Significant correlation was observed between VEGF-C and tumor grade, lymph node metastasis or clinical stage (p<0.01, respectively). These results indicate that elevated Pin-1 or VEGF-C expression is more common in infiltrating duct carcinomas with poor prognostic characteristics and is partly associated with an unfavorable outcome. Given the role of cyclin D1 overexpression in oncogenesis of breast, these results suggest that overexpression of Pin-1 and VEGF-C may promote tumor progression and metastasis.</P>

Role of CDK8 and beta-catenin in colorectal adenocarcinoma.

Seo, Jong-Og,Han, Song Iy,Lim, Sung-Chul National Hellenic Research Foundation 2010 ONCOLOGY REPORTS Vol.24 No.1

<P>Colorectal adenocarcinoma is a major cause of morbidity and mortality. The Wnt/beta-catenin pathway plays an important role in colon cancers. However, relatively little is known about the regulatory mechanism of beta-catenin in colon cancers. CDK8 is a cyclin-dependent kinase (CDK) member of the mediator complex that couples transcriptional regulators to the basal transcriptional machinery, and is implicated in the transcriptional regulation of key pathways involved in colon cancers. To determine the relationship between CDK8 and beta-catenin expressions, a population-based study was conducted for immunohistochemical staining analysis of tumor tissues, and Western blot analysis and CDK8 interference studies of colon cancer cell lines. The hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes was tested. Among 127 colorectal cancers, CDK8 expression was detected in 96 (76%) tumors by immunohistochemistry. CDK8 and beta-catenin expression had significant positive correlation with carcinogenesis, tumor progression and patient survival. Immunohistochemically, CDK8 expression in colorectal cancer was independently associated with beta-catenin activation (P=0.0002). However, beta-catenin expression was not completely suppressed by CDK8 interference in the colon cancer cell lines HCT-116, HT-29 and SNU-C5. These data support a potential link between CDK8 and beta-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis. However, control of CDK8 is not an effective therapeutic strategy through beta-catenin regulation of general colon cancer.</P>

Vibrio vulnificus Metalloprotease VvpE has no Direct Effect on Iron-uptake from Human Hemoglobin

Sun, Hui-Yu,Han, Song-Iy,Choi, Mi-Hwa,Kim, Seong-Jung,Kim, Choon-Mee,Shin, Sung-Heui The Microbiological Society of Korea 2006 The journal of microbiology Vol.44 No.5

This study was designed to determine whether or not Vibrio vulnificus metalloprotease VvpE can promote iron uptake via the proteolytic cleavage of human hemoglobin. We found that V. vulnificus utilized hemoglobin as an iron source more efficiently via the vulnibactin-mediated iron-uptake system than via the HupA-mediated iron-uptake system and, of the proteases produced by V. vulnificus, VvpE was found to be the only protease capable of destroying hemoglobin. However, VvpE expression, on both the transcriptional and protein levels, was suppressed in iron-limited media. However, vvpE transcription, but not extracellular VvpE production, was reactivated by the addition of hemoglobin or inorganic iron into iron-limited media. Moreover, vvpE transcription began only in the late growth phase when V. vulnificus had already consumed most of the iron for growth. In addition, neither vvpE mutation nor in trans vvpE complementation affected the ability of V. vulnificus to acquire iron or to grow in iron-limited media or in cirrhotic ascites containing hemoglobin. Hemoglobin added into iron-limited media was not destroyed, but gradually formed an insoluble aggregate during culture; this aggregation of hemoglobin occurred regardless of vvpE mutation or complementation. These results indicate that VvpE is not required for efficient iron uptake from hemoglobin. On the contrary, hemoglobin or iron is required for efficient vvpE transcription. In addition, a discrepancy exists between vvpE transcription and extracellular VvpE production in iron-limited media containing inorganic iron or hemoglobin, which suggests that additional unknown posttranscriptional events may be involved in the extracellular production of VvpE.

Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death

LIM, SUNG-CHUL,HAN, SONG IY Spandidos Publications 2015 Oncology Reports Vol.34 No.3

<P>Carcinoma cells that have acquired drug resistance often exhibit cross-resistance to various other cytotoxic stimuli. Here, we investigated the effects of ursodeoxycholic acid (UDCA), a gastrointestinal tumor-suppressor, on a cisplatin?resistant SNU601 gastric cancer subline (SNU601/R). While other anticancer drugs, including L-OHP, etoposide, and death ligand TRAIL, had minimal effects on the viability of these resistant cells, they were sensitive to UDCA. The UDCA?induced reduction in the viability of the SNU601/R cells was accomplished through autophagy while the primary means of cell death in the parental SNU601 cells (SNU601/WT) was apoptosis. Previously, we demonstrated that the UDCA-triggered apoptosis of gastric cancer cells was regulated by a cell surface death receptor, TRAIL-R2/DR5, which was upregulated and re-distributed on lipid rafts. The UDCA stimulation of TRAIL-R2/DR5 also occurred in the SNU601/R cells despite the lack of apoptosis. In the present study, we found that CD95/Fas, another cell surface death receptor, was also translocated into lipid rafts in response to UDCA although it was not involved in the decrease in cell viability. Specifically, raft relocalization of CD95/Fas was triggered by UDCA in the SNU601/WT cells in which apoptosis occurred, but not in the SNU601/R cells where autophagic death occurred. Notably, UDCA reduced ATG5 levels, an essential component of autophagy, in the SNU601/WT, but not in the SNU601/R cell line. Moreover, in CD95/Fas-silenced SNU601/WT cells, UDCA did not decrease ATG5 levels and induced autophagic cell death rather than apoptosis. These results imply that raft?distributed CD95/Fas may support UDCA-induced apoptosis via downregulation of ATG5 levels, preventing the autophagic pathway. Taken together, these results suggest that UDCA induces both apoptotic and autophagic cell death depending on the intracellular signaling environment, thereby conferring the advantage to overcome drug resistance through apoptotic defects.</P>

Extracellular acidity enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via DR5 in gastric cancer cells

Hong, Ran,Han, Song Iy The Korean Society of Pharmacology 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.5

The tumor microenvironment greatly influences cancer cell characteristics, and acidic extracellular pH has been implicated as an essential factor in tumor malignancy and the induction of drug resistance. Here, we examined the characteristics of gastric carcinoma (GC) cells under conditions of extracellular acidity and attempted to identify a means of enhancing treatment efficacy. Acidic conditions caused several changes in GC cells adversely affecting chemotherapeutic treatment. Extracellular acidity did inhibit GC cell growth by inducing cell cycle arrest, but did not induce cell death at pH values down to 6.2, which was consistent with down-regulated cyclin D1 and up-regulated p21 mRNA expression. Additionally, an acidic environment altered the expression of atg5, HSPA1B, collagen XIII, collagen XXAI, slug, snail, and zeb1 genes which are related to regulation of cell resistance to cytotoxicity and malignancy, and as expected, resulted in increased resistance of cells to multiple chemotherapeutic drugs including etoposide, doxorubicin, daunorubicin, cisplatin, oxaliplatin and 5-FU. Interestingly, however, acidic environment dramatically sensitized GC cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Consistently, the acidity at pH 6.5 increased mRNA levels of DR4 and DR5 genes, and also elevated protein expression of both death receptors as detected by immunoblotting. Gene silencing analysis showed that of these two receptors, the major role in this effect was played by DR5. Therefore, these results suggest that extracellular acidity can sensitize TRAIL-mediated apoptosis at least partially via DR5 in GCs while it confers resistance to various type of chemotherapeutic drugs.