Publications by authors named "Yoon Sun Lee"

11 Publications

  • Page 1 of 1

p53-dependent glutamine usage determines susceptibility to oxidative stress in radioresistant head and neck cancer cells.

Cell Signal 2021 01 31;77:109820. Epub 2020 Oct 31.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

The manner in which p53 maintains redox homeostasis and the means by which two key metabolic elements, glucose and glutamine, contribute to p53-dependent redox stability remain unclear. To elucidate the manner in which p53 deals with glucose-deprived, reactive oxygen species (ROS)-prone conditions in this regard, two isogenic cancer subclones (HN3R-A and HN3R-B) bearing distinct p53 mutations as an in vitro model of intratumoral p53 heterogeneity were identified. Following cumulative irradiation, the subclones showed a similar metabolic shift to aerobic glycolysis and increasing NADPH biogenesis for cellular defense against oxidative damage irrespective of p53 status. The radioresistant cancer cells became more sensitive to glycolysis-targeting drugs. However, in glucose-deprived and ROS-prone conditions, HN3R-B, the subclone with the original p53 increased the utilization of glutamine by GLS2, thereby maintaining redox homeostasis and ATP. Conversely, HN3R-A, the p53-deficient radioresistant subclone displayed an impairment in glutamine usage and high susceptibility to metabolic stresses as well as ROS-inducing agents despite the increased ROS scavenging system. Collectively, our findings suggest that p53 governs the alternative utilization of metabolic ingredients, such as glucose and glutamine, in ROS-prone conditions. Thus, p53 status may be an important biomarker for selecting cancer treatment strategies, including metabolic drugs and ROS-inducing agents, for recurrent cancers after radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cellsig.2020.109820DOI Listing
January 2021

p53/BNIP3-dependent mitophagy limits glycolytic shift in radioresistant cancer.

Oncogene 2019 05 21;38(19):3729-3742. Epub 2019 Jan 21.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

The role of p53 in genotoxic therapy-induced metabolic shift in cancers is not yet known. In this study, we investigated the role of p53 in the glycolytic shift in head and neck squamous cell carcinoma cell lines following irradiation. Isogenic p53-null radioresistant cancer cells established through cumulative irradiation showed decreased oxygen consumption and increased glycolysis with compromised mitochondria, corresponding with their enhanced sensitivity to drugs that target glycolysis. In contrast, radioresistant cancer cells with wild-type p53 preserved their primary metabolic profile with intact mitophagic processes and maintained their mitochondrial integrity. Moreover, we identified a previously unappreciated link between p53 and mitophagy, which limited the glycolytic shift through the BNIP3-dependent clearance of abnormal mitochondria. Thus, drugs targeting glycolysis could be used as an alternative strategy for overcoming radioresistant cancers, and the p53 status could be used as a biomarker for selecting participants for clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-019-0697-6DOI Listing
May 2019

Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer.

Oral Oncol 2018 03 20;78:56-63. Epub 2018 Feb 20.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Objectives: PI3K/Akt/mTOR pathway is commonly activated in most cancers and is correlated with resistance to anticancer therapies such as radiotherapy. Therefore, PI3K is an attractive target for treating PI3K-associated cancers.

Material And Methods: We investigated the basal expression and the expression after treatment of PI3K inhibitor or Src inhibitor of PI3K/Akt pathway-related proteins in AMC-HN3, AMC-HN3R, HN30 and HN31 cells by performing immunoblotting analysis. The sensitivity to PI3K inhibitors or Src inhibitor was analyzed by MTT assay and clonogenic assay. To determine the antitumoral activity of combination treatment with PI3K inhibitor and Src inhibitor, we used using xenograft mouse model.

Results: We found that PI3K regulatory subunit p85 was predominantly phosphorylated in radioresistant head and neck cancer cell line (HN31), which showed resistance to PI3K inhibitors. Next, we investigated mechanism through which PI3K p85 phosphorylation modulated response to PI3K inhibitors. Of note, constitutive activation of Src was found in HN31 cells and upon PI3K inhibitor treatment, restoration of p-Src was occurred. Src inhibitor improved the efficacy of PI3K inhibitor treatment and suppressed the reactivation of both Src and PI3K p85 in HN31 cells. Furthermore, downregulation of PI3K p85 expression by using a specific siRNA suppressed Src phosphorylation.

Conclusions: Together, our results imply the novel role of the PI3K regulatory subunit p85 in the development of resistance to PI3K inhibitors and suggest the presence of a regulatory loop between PI3K p85 and Src in radioresistant head and neck cancers with constitutively active PI3K/Akt pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2018.01.014DOI Listing
March 2018

Subclinical Hypothyroidism in Childhood Cancer Survivors.

Yonsei Med J 2016 Jul;57(4):915-22

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea.

Purpose: In childhood cancer survivors, the most common late effect is thyroid dysfunction, most notably subclinical hypothyroidism (SCH). Our study evaluated the risk factors for persistent SCH in survivors.

Materials And Methods: Survivors (n=423) were defined as patients who survived at least 2 years after cancer treatment completion. Thyroid function was assessed at this time and several years thereafter. Two groups of survivors with SCH were compared: those who regained normal thyroid function during the follow-up period (normalized group) and those who did not (persistent group).

Results: Overall, 104 of the 423 survivors had SCH. SCH was observed in 26% of brain or nasopharyngeal cancer survivors (11 of 43) and 21.6% of leukemia survivors (35 of 162). Sixty-two survivors regained normal thyroid function, 30 remained as persistent SCH, and 12 were lost to follow-up. The follow-up duration was 4.03 (2.15-5.78) years. Brain or nasopharyngeal cancer and Hodgkin disease were more common in the persistent group than in the normalized group (p=0.002). More patients in the persistent group received radiation (p=0.008). Radiation to the head region was higher in this group (2394±2469 cGy) than in the normalized group (894±1591 cGy; p=0.003). On multivariable analysis, lymphoma (p=0.011), brain or nasopharyngeal cancer (p=0.039), and head radiation dose ≥1800 cGy (p=0.039) were significant risk factors for persistent SCH.

Conclusion: SCH was common in childhood cancer survivors. Brain or nasopharyngeal cancer, lymphoma, and head radiation ≥1800 cGy were significant risk factors for persistent SCH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3349/ymj.2016.57.4.915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951468PMC
July 2016

Symptom Interval and Patient Delay Affect Survival Outcomes in Adolescent Cancer Patients.

Yonsei Med J 2016 May;57(3):572-9

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea.

Purpose: Unique features of adolescent cancer patients include cancer types, developmental stages, and psychosocial issues. In this study, we evaluated the relationship between diagnostic delay and survival to improve adolescent cancer care.

Materials And Methods: A total of 592 patients aged 0-18 years with eight common cancers were grouped according to age (adolescents, ≥10 years; children, <10 years). We retrospectively reviewed their symptom intervals (SIs, between first symptom/sign of disease and diagnosis), patient delay (PD, between first symptom/sign of disease and first contact with a physician), patient delay proportion (PDP), and overall survival (OS).

Results: Mean SI was significantly longer in adolescents than in children (66.4 days vs. 28.4 days; p<0.001), and OS rates were higher in patients with longer SIs (p=0.001). In children with long SIs, OS did not differ according to PDP (p=0.753). In adolescents with long SIs, OS was worse when PDP was ≥0.6 (67.2%) than <0.6 (95.5%, p=0.007). In a multivariate analysis, adolescents in the long SI/PDP ≥0.6 group tended to have a higher hazard ratio (HR, 6.483; p=0.069) than those in the long SI/PDP <0.6 group (HR=1, reference).

Conclusion: Adolescents with a long SI/PDP ≥0.6 had lower survival rates than those with a short SI/all PDP or a long SI/PDP <0.6. They should be encouraged to seek prompt medical assistance by a physician or oncologist to lessen PDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3349/ymj.2016.57.3.572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800344PMC
May 2016

Poor bone health at the end of puberty in childhood cancer survivors.

Pediatr Blood Cancer 2015 Oct 13;62(10):1838-43. Epub 2015 May 13.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea.

Background: Although the survival rate following childhood cancer is >80%, late effects are a major concern. We aimed to determine the clinical factors affecting bone health after puberty in childhood cancer survivors at risk for low bone mineral density (BMD).

Procedures: We performed dual-energy X-ray absorptiometry at the lumbar spine, femoral neck, and total hip regions for survivors with the following bone densitometry indications (BDIXs): brain or nasopharyngeal cancer, head or neck area radiotherapy, or corticosteroid treatment (N = 92). Additionally, we evaluated 16 survivors without these BDIXs but with other clinical factors that could affect bone health. We assessed the effects of these factors on BMD using univariate and logistic regression analyses. Moderate BMD deficit was defined as a Z-score of <-1.0 and ≥-2.0, and severe BMD deficit was defined as <-2.0.

Results: Severe BMD deficits were found in 18 survivors (16.7%) and moderate BMD deficits were in 39 (36.1%) in at least one bone region. BMD deficits tended to increase as the number of BDIXs increased (P < 0.010). There were no severe BMD deficits in survivors without BDIXs. The duration since cancer treatment completion was correlated with higher BMD (P < 0.05). Endocrine dysfunction was a significant risk factor for decreased BMD in univariate and multivariate analyses (P < 0.05 for both).

Conclusions: Decreased BMD was prevalent in our study cohort. Endocrine dysfunction was found to be a significant risk factor, and it should be managed in survivors to ensure future bone health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.25581DOI Listing
October 2015

Giant osteochondroma of the parapharyngeal space: a case report.

J Korean Assoc Oral Maxillofac Surg 2013 Feb 21;39(1):35-40. Epub 2013 Feb 21.

Department of Oral and Maxillofacial Surgery, School of Dentistry, Dankook University, Cheonan, Korea.

Osteochondroma is a common benign tumor of the axial skeleton, especially in the distal metaphysis of the femur and the proximal metaphysis of the tibia, that can occur on the facial skeleton (albeit rarely). Osteochondroma is differentiated from chondroma, osteochondromatosis and osteoma. Osteochondroma shows an irregular radiopaque lesion and chondromatic area surrounded by the osteoma. When it develops in the long bone, it has a marked tendency to occur at 10 to 20 years of age and ceases with the end of pubertal growth. However, when it develops in the mandibular condyle, it is prevalent in the third decade and continuous to develop. Tumors that develop in the long bone have a predilection for men, but tumors in the mandible have a predilection for women. In osteochondroma of the mandibular condyle, clinical features presented include occlusal changes, facial asymmetry, headaches, pain and joint noise on the temporomandibular joint, mouth opening limitations, and jaw deviation at the involved site. The first choice of treatment for the massive osteochondroma is surgical removal. A 70-year-old female patient with an osteochondroma on her right mandibular condyle visited our clinic. We surgically removed the mass with favorable results. It is presented here along with a review of literature on osteochondroma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5125/jkaoms.2013.39.1.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858154PMC
February 2013

Radioresistant cancer cells can be conditioned to enter senescence by mTOR inhibition.

Cancer Res 2013 Jul 30;73(14):4267-77. Epub 2013 May 30.

Department of Biochemistry and Molecular Biology, Otolaryngology, and Biomedical Research Center, Asan Medical Center, University of Ulsan, Ulsan, Korea.

Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated β-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated β-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-12-3516DOI Listing
July 2013

Effective relief of neuropathic pain by adeno-associated virus-mediated expression of a small hairpin RNA against GTP cyclohydrolase 1.

Mol Pain 2009 Nov 18;5:67. Epub 2009 Nov 18.

Departments of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.

Background: Recent studies show that transcriptional activation of GTP cyclohydrolase I (GCH1) in dorsal root ganglia (DRG) is significantly involved in the development and persistency of pain symptoms. We thus hypothesize that neuropathic pain may be attenuated by down-regulation of GCH1 expression, and propose a gene silencing system for this purpose.

Results: To interrupt GCH1 synthesis, we designed a bidirectional recombinant adeno-associated virus encoding both a small hairpin RNA against GCH1 and a GFP reporter gene (rAAV-shGCH1). After rAAV-shGCH1 was introduced into the sciatic nerve prior to or following pain-inducing surgery, therapeutic efficacy and the underlying mechanisms were subsequently validated in animal models. The GFP expression data indicates that rAAV effectively delivered transgenes to DRG. Subsequently reduced GCH1 expression was evident from immunohistochemistry and western-blotting analysis. Along with the down-regulation of GCH1, the von Frey test correspondingly indicated a sharp decline in pain symptoms upon both pre- and post-treatment with rAAV-shGCH1. Interestingly, GCH1 down-regulation additionally led to decreased microglial activation in the dorsal horn, implying an association between pain attenuation and reduced inflammation.

Conclusion: Therefore, the data suggests that GCH1 levels can be reduced by introducing rAAV-shGCH1, leading to pain relief. Based on the results, we propose that GCH1 modulation may be developed as a clinically applicable gene therapy strategy to treat neuropathic pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1744-8069-5-67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785765PMC
November 2009

Autophagic death of adult hippocampal neural stem cells following insulin withdrawal.

Stem Cells 2008 Oct 24;26(10):2602-10. Epub 2008 Jul 24.

Departments of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824, USA.

Novel therapeutic approaches using stem cell transplantation to treat neurodegenerative diseases have yielded promising results. However, survival of stem cells after transplantation has been very poor in animal models, and considerable efforts have been directed at increasing the viability of engrafted stem cells. Therefore, understanding the mechanisms that regulate survival and death of neural stem cells is critical to the development of stem cell-based therapies. Hippocampal neural (HCN) stem cells derived from the adult rat brain undergo cell death following insulin withdrawal, which is associated with downregulation of antiapoptotic Bcl-2 family members. To understand the type of cell death in HCN cells following insulin withdrawal, apoptosis markers were assessed. Of note, DNA fragmentation or caspase-3 activation was not observed, but rather dying cells displayed features of autophagy, including increased expression of Beclin 1 and the type II form of light chain 3. Electron micrographs showed the dramatically increased formation of autophagic vacuoles with cytoplasmic contents. Staurosporine induced robust activation of caspase-3 and nucleosomal DNA fragmentation, suggesting that the machinery of apoptosis is intact in HCN cells despite the apparent absence of apoptosis following insulin withdrawal. Autophagic cell death was suppressed by knockdown of autophagy-related gene 7, whereas promotion of autophagy by rapamycin increased cell death. Taken together, these data demonstrate that HCN cells undergo a caspase-independent, autophagic cell death following insulin withdrawal. Understanding the mechanisms governing autophagy of adult neural stem cells may provide novel strategies to improve the survival rate of transplanted stem cells for treatment of neurodegenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/stemcells.2008-0153DOI Listing
October 2008

[Clinical features of fulminant hepatic failure in a tertiary hospital with a liver transplant center in Korea].

Korean J Hepatol 2006 Mar;12(1):82-92

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background/aims: Striking geographic differences have been noted in the etiology of fulminant hepatic failure (FHF). The prognosis of patients with FHF who do not receive liver transplantation in a timely manner is quite dismal. This study intended to identify the etiology and outcome of FHF in Korean adults and to examine the role of urgent living-donor liver transplantation (LDLT) for treating this unique situation.

Methods: We identified all the adult FHF patients who were referred to our unit between 1999 and 2004. FHF was defined as severe acute hepatitis complicated by the rapid development of hepatic encephalopathy within 8 weeks of the initial symptoms in the patients without a previous history of liver disease.

Results: One hundred fourteen patients (47 males and 67 females) were identified. The mean age was 39.5+/-15.3 years. Drugs were the most common cause (28.1%) of FHF (herbal medications, 9.6%), and acute viral infection accounted for 23.7% (HBV accounted for 15.8%). Indeterminate etiologies were noted in 34%. The 90-day survival rate of the nontransplant group was only 15%. Fourteen patients received liver transplants (13 right-lobe LDLT, 1 cadaveric whole liver), and 12 of these (85.7%) survived and showed good graft function during 22 months of median follow-up.

Conclusions: Although the causes of FHF in Korea were diverse, HBV infection and herbal medications were responsible for a significant proportion of the cases. Since urgent LDLT improved the overall survival rate of patients with FHF, this should be considered as an important treatment option for patients suffering with FHF.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2006
-->