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Zhang T.,Research Institute for Medical Science | Li Y.,Research Institute for Medical Science | Park K.A.,Research Institute for Medical Science | Byun H.S.,Research Institute for Medical Science | And 12 more authors.
Autophagy | Year: 2012

Targeted disruption of STAT3 function has proven to be a useful cancer therapeutic approach by inducing apoptotic cell death. Cucurbitacin is currently under development as a small molecule of STAT3 inhibitor to trigger cell death in many cancers. Here, we systematically studied the molecular mechanisms underlying cucurbitacin-induced cell death, in particular the involvement of autophagy. Treatment with cucurbitacin resulted in non-apoptotic cell death in a caspase-independent manner. Notably, cucurbitacin enhanced excessive conversion of lipidated LC3 (LC3-II) and accumulation of autophagosomes in many cell types. Such autophagy and cell death induced by cucurbitacin were independent of its ability to inhibit STAT3 function, but mainly mediated by enhanced production of mitochondrial-derived reactive oxygen species (ROS), and subsequently activation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). Interestingly, both the autophagy inhibitor wortmannin and knockdown of Atg5 or Beclin 1 failed to rescue the cells from cucurbitacin-induced cell death, as suppression of autophagy induced the mode of cell death to shift from autophagic cell death to caspase-dependent apoptosis. Thus the present study provides new insights into the molecular mechanisms underlying cucurbitacin-mediated cell death and supports cucurbitacin as a potential anti-cancer drug through modulating the balance between autophagic and apoptotic modes of cell death. © 2012 Landes Bioscience.


Jung C.-W.,Research Institute for Medical science | Suh K.-S.,Research Institute for Medical science | Lee J.-S.,Chungnam National University | Kim J.-R.,Chungnam National University | And 3 more authors.
Journal of Breast Cancer | Year: 2010

Purpose: Phyllodes tumors (PTs) of the breast have been classified as benign, borderline, or malignant based on their histopathologic features. However, predicting clinical behavior based on these features has proven to be difficult given that local recurrence occurs in both benign and malignant PTs. Recurrence has been shown to mirror the histologic pattern of the primary tumor or to show dedifferentiation. The aim of this study was to assess the value of the histopathologic parameters, expression or mutation of c-Kit and platelet derived growth factor receptor alpha (PDGFRA) in predicting tumor recurrence. Methods: Representative areas from 39 benign, 16 borderline, and 12 malignant PTs were selected for construction of tissue microarrays. Immunohistochemical analyses for p53, Ki-67, c-Kit, and PDGFRA were performed and SSCP-PCR analysis was carried out to identify mutations in exons 9, 11, 13, and 17 of the c-Kit gene and exons 12 and 18 of the PDGFRA gene. Clinicopathologic features, including tumor recurrence and margin status, were also evaluated. Results: Of the 67 PTs, 11 cases (16.4%) recurred from 3 to 92 months following initial diagnosis (4 benign, 2 borderline, and 5 malignant). One benign PT case recurred as a borderline tumor and two borderline PT cases recurred as malignancies. Three patients died of malignant PT. No mutations of the c-Kit or PDGFRA genes were found and there was no statistically significant association of either p53 or p16 immunostaining with recurrent disease (p>0.05). However, histologic grade (p=0.033), margin status (p< 0.001), Ki-67 (p=0.012), c-Kit (p=0.002), and PDGFRA (p= 0.007) stromal immunopositivity were significantly correlated with recurrence. Conclusion: Even though positive or close margins were significantly associated with tumor recurrence, stromal c-Kit, PDGFRA positivity, and the Ki-67 index were useful for predicting recurrent PTs. Despite this, no c-Kit or PDGFRA mutations were found.


Park J.,Research Institute for Medical science | Kim J.-M.,Research Institute for Medical science | Park J.K.,Chungnam National University | Huang S.,Research Institute for Medical science | And 4 more authors.
Head and Neck | Year: 2015

Background This study investigated the role of p21-activated kinase (PAK)-1 in progression of head and neck squamous cell carcinoma (HNSCC). Methods We examined PAK isoforms and explored whether PAK activation enhanced in vitro invasion of the HNSCC cell line. We analyzed the relationship between PAK1 expression and various clinicopathological features and investigated the effect of PAK1 overexpression on survival in 119 patients with HNSCC. Results PAK1 and PAK2 are predominantly expressed in HNSCC cells and patient tissues. Particularly, PAK1 makes the dominant contribution to increase in cell migration and invasion. There was a statistically significant correlation between PAK1 overexpression and aggressive cancer behavior. Moreover, PAK1 seemed to be a prognostic factor for overall and disease-specific survival in patients. Interestingly, enhancement of PAK1 expression was found in the invasive front of cancer. Conclusion PAK1 is associated with the aggressive tumor behavior and poor prognosis of head and neck cancer. © 2014 Wiley Periodicals, Inc.


Lee Y.S.,Korea Institute of Toxicology | Oh J.-H.,Korea Institute of Toxicology | Yoon S.,Korea Institute of Toxicology | Kwon M.-S.,Korea Institute of Toxicology | And 8 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: Despite the widespread use of radiotherapy as a local and regional modality for the treatment of cancer, some non-small-cell lung cancers commonly develop resistance to radiation. We thus sought to clarify the molecular mechanisms underlying resistance to radiation. Methods and Materials: We established the radioresistant cell line H460R from radiosensitive parental H460 cells. To identify the radioresistance-related genes, we performed microarray analysis and selected several candidate genes. Results: Clonogenic and MTT assays showed that H460R was 10-fold more resistant to radiation than H460. Microarray analysis indicated that the expression levels of 1,463 genes were altered more than 1.5-fold in H460R compared with parental H460. To evaluate the putative functional role, we selected one interesting gene tumor protein p53-inducible protein 3 (TP53I3), because that this gene was significantly downregulated in radioresistant H460R cells and that it was predicted to link p53-dependent cell death signaling. Interestingly, messenger ribonucleic acid expression of TP53I3 differed in X-ray-irradiated H460 and H460R cells, and overexpression of TP53I3 significantly affected the cellular radiosensitivity of H460R cells. Conclusions: These results show that H460R may be useful in searching for candidate genes that are responsible for radioresistance and elucidating the molecular mechanism of radioresistance. © 2010 Elsevier Inc. All rights reserved.


Lee H.,Research Institute for Medical Science | Jeon J.,Research Institute for Medical Science | Ryu Y.S.,Research Institute for Medical Science | Jeong J.E.,Research Institute for Medical Science | And 5 more authors.
Journal of Korean Medical Science | Year: 2010

The massive reorganization of microtubule network involves in transcriptional regulation of several genes by controlling transcriptional factor, nuclear factor-kappa B (NF-κB) activity. The exact molecular mechanism by which microtubule rearrangement leads to NF-κB activation largely remains to be identified. However microtubule disrupting agents may possibly act in synergy or antagonism against apoptotic cell death in response to conventional chemotherapy targeting DNA damage such as adriamycin or comptothecin in cancer cells. Interestingly pretreatment of microtubule disrupting agents (colchicine, vinblastine and nocodazole) was observed to lead to paradoxical suppression of DNA damage-induced NF-κB binding activity, even though these could enhance NF-κB signaling in the absence of other stimuli. Moreover this suppressed NF-κB binding activity subsequently resulted in synergic apoptotic response, as evident by the combination with Adr and low doses of microtubule disrupting agents was able to potentiate the cytotoxic action through caspase-dependent pathway. Taken together, these results suggested that inhibition of microtubule network chemosensitizes the cancer cells to die by apoptosis through suppressing NF-κB DNA binding activity. Therefore, our study provided a possible anti-cancer mechanism of microtubule disrupting agent to overcome resistance against to chemotherapy such as DNA damaging agent. © 2010 The Korean Academy of Medical Sciences.


Silwal P.,Research Institute for Medical science | Lee M.-N.,Chungnam National University | Lee C.-J.,Chungnam National University | Hong J.-H.,Chungnam National University | And 7 more authors.
Korean Journal of Physiology and Pharmacology | Year: 2012

Mast cells are involved in allergic responses, protection against pathogens and autoimmune diseases. Dexamethasone (Dex) and other glucocorticoids suppress FceRI-mediated release of inflammatory mediators from mast cells. The inhibition mechanisms were mainly investigated on the downstream signaling of Fc receptor activations. Here, we addressed the effects of Dex on Fc receptor expressions in rat mast cell line RBL-2H3. We measured mRNA levels of Fc receptors by real-time PCR. As expected, Dex decreased the mRNA levels of activating Fc receptor for IgE (FceR) I and increased the mRNA levels of the inhibitory Fc receptor for IgG FcRIIb. Interestingly, Dex stimulated transcriptions of other activating receptors such as Fc receptors for IgG (FcR) I and FcRIII. To investigate the mechanisms underlying transcriptional regulation, we employed a transcription inhibitor actinomycin D and a translation inhibitor cycloheximide. The inhibition of protein synthesis without Dex treatment enhanced FcRI and FcRIII mRNA levels potently, while FceRI and FcRIIb were minimally affected. Next, we examined expressions of the Fc receptors on cell surfaces by the flow cytometric method. Only FcRIIb protein expression was significantly enhanced by Dex treatment, while FcRI, FcRIII and FceRI expression levels were marginally changed. Our data showed, for the first time, that Dex regulates Fc receptor expressions resulting in augmentation of the inhibitory receptor FcRIIb.


Jo Y.-J.,Chungnam National University | Kim K.-N.,Chungnam National University | Lee Y.-H.,Chungnam National University | Kim J.-Y.,Chungnam National University | And 2 more authors.
Ophthalmic Surgery Lasers and Imaging | Year: 2010

Currently, many surgeons use bicanalicular silicone tubes as a stent to keep the intranasal mucosal ostium patent when they perform endoscopic dacryocystorhinostomy. The authors describe the sleeve technique using bicanalicular silicone tubes. After inserting the bicanalicular silicone tube, a sleeve is passed over it. The sleeve prevents the nasal mucosa from obstructing the intranasal mucosal ostium and enlarges the mucosal ostium. In primary acquired nasolacrimal duct obstruction, the sleeve technique was applied to 61 cases (group 1); the other 75 cases (group 2) were intubated by bicanalicular silicone tube only. The overall success rate was 95.1% in group 1 and 90.7% in group 2 (P = .51), and the average mucosal ostium at 6 months postoperatively was 3.2 ± 1.1 and 1.9 ± 1.0 mm (P = .04), respectively. The authors believe that the sleeve technique has the advantage of maintaining a larger intranasal mucosal ostium. Copyright © SLACK Incorporated.


PubMed | Research Institute for Medical Science
Type: Journal Article | Journal: Journal of Korean medical science | Year: 2010

The massive reorganization of microtubule network involves in transcriptional regulation of several genes by controlling transcriptional factor, nuclear factor-kappa B (NF-B) activity. The exact molecular mechanism by which microtubule rearrangement leads to NF-B activation largely remains to be identified. However microtubule disrupting agents may possibly act in synergy or antagonism against apoptotic cell death in response to conventional chemotherapy targeting DNA damage such as adriamycin or comptothecin in cancer cells. Interestingly pretreatment of microtubule disrupting agents (colchicine, vinblastine and nocodazole) was observed to lead to paradoxical suppression of DNA damage-induced NF-B binding activity, even though these could enhance NF-B signaling in the absence of other stimuli. Moreover this suppressed NF-B binding activity subsequently resulted in synergic apoptotic response, as evident by the combination with Adr and low doses of microtubule disrupting agents was able to potentiate the cytotoxic action through caspase-dependent pathway. Taken together, these results suggested that inhibition of microtubule network chemosensitizes the cancer cells to die by apoptosis through suppressing NF-B DNA binding activity. Therefore, our study provided a possible anti-cancer mechanism of microtubule disrupting agent to overcome resistance against to chemotherapy such as DNA damaging agent.


PubMed | Research Institute for Medical Science
Type: Journal Article | Journal: Autophagy | Year: 2012

Targeted disruption of STAT3 function has proven to be a useful cancer therapeutic approach by inducing apoptotic cell death. Cucurbitacin is currently under development as a small molecule of STAT3 inhibitor to trigger cell death in many cancers. Here, we systematically studied the molecular mechanisms underlying cucurbitacin-induced cell death, in particular the involvement of autophagy. Treatment with cucurbitacin resulted in non-apoptotic cell death in a caspase-independent manner. Notably, cucurbitacin enhanced excessive conversion of lipidated LC3 (LC3-II) and accumulation of autophagosomes in many cell types. Such autophagy and cell death induced by cucurbitacin were independent of its ability to inhibit STAT3 function, but mainly mediated by enhanced production of mitochondrial-derived reactive oxygen species (ROS), and subsequently activation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). Interestingly, both the autophagy inhibitor wortmannin and knockdown of Atg5 or Beclin 1 failed to rescue the cells from cucurbitacin-induced cell death, as suppression of autophagy induced the mode of cell death to shift from autophagic cell death to caspase-dependent apoptosis. Thus the present study provides new insights into the molecular mechanisms underlying cucurbitacin-mediated cell death and supports cucurbitacin as a potential anti-cancer drug through modulating the balance between autophagic and apoptotic modes of cell death.

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