• The Korean Journal of Physiology and Pharmacology
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• 제18권6호
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• pp.509-516
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• 2014

Radiation therapy for variety of human solid tumors utilizes mechanism of cell death after DNA damage caused by radiation. In response to DNA damage, cytochrome c was released from mitochondria by activation of pro-apoptotic Bcl-2 family proteins, and then elicits massive $Ca^{2+}$ release from the ER that lead to cell death. It was also suggested that irradiation may cause the deregulation of $Ca^{2+}$ homeostasis and trigger programmed cell death and regulate death specific enzymes. Thus, in this study, we investigated how cellular $Ca^{2+}$ metabolism in RKO cells, in comparison to radiation-resistant A549 cells, was altered by gamma (${\gamma}$)-irradiation. In irradiated RKO cells, $Ca^{2+}$ influx via activation of NCX reverse mode was enhanced and a decline of $[Ca^{2+}]_i$ via forward mode was accelerated. The amount of $Ca^{2+}$ released from the ER in RKO cells by the activation of $IP_3$ receptor was also enhanced by irradiation. An increase in $[Ca^{2+}]_i$ via SOCI was enhanced in irradiated RKO cells, while that in A549 cells was depressed. These results suggest that ${\gamma}$-irradiation elicits enhancement of cellular $Ca^{2+}$ metabolism in radiation-sensitive RKO cells yielding programmed cell death.

• Asian Pacific Journal of Cancer Prevention
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• 제16권16호
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• pp.7261-7266
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• 2015

Breast cancer, the most common cancer in the women, is the leading cause of death. Necrotic signaling pathways will enable targeted therapeutic agents to eliminate apoptosis-resistant cancer cells. In the present study, the effect of shikonin on the induction of cell necroptosis or apoptosis was evaluated using the T-47D breast cancer cell line. The cell death modes, caspase-3 and 8 activities and the levels of reactive oxygen species (ROS) were assessed. Cell death mainly occurred through necroptosis. In the presence of Nec-1, caspase-3 mediated apoptosis was apparent in the shikonin treated cells. Shikonin stimulates ROS generation in the mitochondria of T-47D cells, which causes necroptosis or apoptosis. Induction of necroptosis, as a backup-programmed cell death pathway via ROS stimulation, offers a new strategy for the treatment of breast cancer.

• Journal of Microbiology and Biotechnology
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• 제19권8호
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• pp.803-809
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• 2009

Recent evidence has revealed the occurrence of an apoptotic phenotype in Candida albicans that is inducible with environmental stresses such as acetic acid, hydrogen peroxide, and amphotericin B. In the present study, we found that the Chinese herbal medicine Baicalein (BE), which was one of the skullcapflavones, can induce apoptosis in C. albicans. The apoptotic effects of BE were detected by flow cytometry using Annexin V-FITC and DAPI, and it was confirmed by transmission electron microscopy analysis. After exposure to 4 ${\mu}g$/ml BE for 12 h, about 10% of C. albicans cells were apoptotic. Both the increasing intracellular levels of reactive oxygen species (ROS) and upregulation of some redox-related genes (CAP1, SOD2, TRR1) were observed. Furthermore, we compared the survivals of CAP1 deleted, wild-type, and overexpressed strains and found that Cap1p attenuated BE-initiated cell death, which was coherent with a higher mRNA level of the CAP1 gene. In addition, the mitochondrial membrane potential of C. albicans cells changed significantly (p<0.001) upon BE treatment compared with control. Taken together, our results indicated that BE treatment induced apoptosis in C. albicans cells, and the apoptosis was associated with the breakdown of mitochondrial membrane potential.

• 미생물학회지
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• 제49권4호
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• pp.301-308
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• 2013

Programmed Death-1 (PD-1)은 중요한 면역조절분자들 중 하나로 다양한 면역활성인자에 자극된 T 세포, B 세포, NKT 세포 및 대식세포에서 발현된다. Lipopolysaccaride (LPS)는 그람음성세균의 세포벽구성물질로 PD-1 발현을 유도하는 중요 면역원들 중 하나로 알려져 있다. 그러나 선천면역세포에서 PD-1 발현기전에 관한 연구는 미비한 실정이다. 본 연구에서는 LPS에 의해 자극된 Raw264.7 세포주를 대상으로 PD-1 발현 및 발현조전기전을 RT-PCR, Western Blot, 유세포분석기, ChIP assay 및 co-immunoprecipitation 방법으로 조사하였다. Raw264.7 세포주가 LPS로 자극되었을 때 PI3K 및 p38 신호전달경로를 경유하여 PD-1 발현이 크게 증가되었다. 또한 LPS 주사된 생쥐의 비장유래 대식세포에서도 PD-1 발현이 증가됨을 확인 하였다. PD-1 유전자의 프로모터 분석을 통해서 NF-${\kappa}B$ 및 IRF-1 결합부위가 PD-1 발현에 중요함을 알 수 있었다. 또한 PD-1 발현을 극대화하기 위하여 전사조절인자 NF-${\kappa}B$ 및 IRF-1의 공동활성이 필수적임을 확인하였다. 본 연구결과는 LPS 유도 생쥐패혈증모델에서 선천면역세포에 발현된 PD-1분자의 제어를 통한 질병 연구에 유용한 자료로 이용될 수 있을 것으로 사료된다.

• BMB Reports
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• 제41권1호
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• pp.11-22
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• 2008

Apoptosis (programmed cell death) is a cellular self-destruction mechanism that is essential for a variety of biological events, such as developmental sculpturing, tissue homeostasis, and the removal of unwanted cells. Mitochondria play a crucial role in regulating cell death. $Ca^{2+}$ has long been recognized as a participant in apoptotic pathways. Mitochondria are known to modulate and synchronize $Ca^{2+}$ signaling. Massive accumulation of $Ca^{2+}$ in the mitochondria leads to apoptosis. The $Ca^{2+}$ dynamics of ER and mitochondria appear to be modulated by the Bcl-2 family proteins, key factors involved in apoptosis. The number and morphology of mitochondria are precisely controlled through mitochondrial fusion and fission process by numerous mitochondria-shaping proteins. Mitochondrial fission accompanies apoptotic cell death and appears to be important for progression of the apoptotic pathway. Here, we highlight and discuss the role of mitochondrial calcium handling and mitochondrial fusion and fission machinery in apoptosis.

• 생명과학회지
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• 제26권7호
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• pp.868-874
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• 2016

수용체 상호작용 단백질 인산화 효소 RIPK1 (Receptor-interacting protein kinases 1)과 RIPK3은 고도로 보존된 인산화 효소 부위를 통하여 세린이나 트레오닌의 하이드록실기를 인산화하는 세린 또는 트레오닌-단백질 인산화 효소 군에 속한다. RIPK군은 염증이나 선천성 면역뿐 만 아니라 세포사멸이나 괴사와 같은 프로그램화된 세포사 멸을 중재하는데 중요한 역할을 담당한다. RIPK1과 다른 TNFR1 관련 단백질들의 상호작용은 TNF 수용체 1(TNFR1)에 사이토카인이 결합할 때 생존 촉진 전사인자 NF-κB의 활성을 조절하는 신호전달복합체 I을 조립하는 것으로 알려져 왔다. 뿐만 아니라, RIPK1과 RIPK3은 프로그램화된 세포괴사를 중재하는 RIP 동형 상호작용 모티브(RHIM)를 통하여 상호작용하고, 이러한 괴사는 세포사멸의 유형과는 다른 형태학적 특징을 가진 돌발적이고 제어되지 않는 세포사멸 유형으로 오랫동안 알려져 왔다. RIPK1과 RIPK3에 존재하는 RHIM의 고도로 보존된 서열들이 이들의 상호작용을 조절하며 이들은 necrosome이라 불리는 세포질 내 아밀로이드 복합체의 조립을 유도 한다. 또한 necrosome은 최근에 하위 신호전달을 조절하는 RIPK3의 기질로 확인된 혼합형 인산화 효소 도메인-유사 단백질(MLKL)을 포함한다. 본 리뷰는 TNF 신호전달에서 RIPK와 MLKL의 기능적, 생리적 특징들에 관한 개요를 제공한다.

• Tuberculosis and Respiratory Diseases
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• 제82권3호
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• pp.227-233
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• 2019

Background: Programmed death-ligand 1 (PD-L1), a transmembrane protein, binds to the programmed death-1 (PD-1) receptor, and anti-PD-1 therapy enables immune responses against tumors. This study aimed to assess clinical characteristics of PD-L1 expression using immunohistochemistry among Korean patients with lung cancer. Methods: We retrospectively reviewed the data of patients with pathologically proven lung cancer from a single institution. PD-L1 expression determined by Tumor Proportion Score (TPS) was detected using 22C3 pharmDx (Agilent Technologies) and SP263 (Ventana Medical Systems) assays. Results: From July 2016 to July 2017, 267 patients were enrolled. The main histologic type was adenocarcinoma (69.3%). Most participants were smokers (67.4%) and had clinical stage IV disease (60.7%). In total, 116 (42%) and 58 (21%) patients had TPS ${\geq}1%$ and ${\geq}50%$, respectively. The patients were significantly older in TPS ${\geq}1%$ group than in TPS <1% group ($64.83{\pm}9.38years$ vs. $61.73{\pm}10.78years$, p=0.014), not in TPS ${\geq}50%$ cutoff value ($64.69{\pm}9.39$ vs. $62.36{\pm}10.51$, p=0.178). Regarding histologic grade, higher proportions of poorly differentiated tumor were observed in the TPS ${\geq}1%$ (40.8% vs. 25.8%, p=0.020) and TPS ${\geq}50%$ groups (53.2% vs. 27.2%, p=0.004). Among 34 patients examined with 22C3 and SP263 assays, 27 had positive results in both assays, with a cutoff of TPS ${\geq}1%$ (r=0.826; 95% confidence interval, 0.736-0.916). Conclusion: PD-L1 expression, defined as TPS ${\geq}1%$, was related to older age and poorly differentiated histology. There was a similar distribution of PD-L1 expression in both 22C3 and SP263 results.

• 대한영상의학회지
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• 제85권2호
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• pp.394-408
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• 2024

목적 CT 영상 소견을 이용하여 편평세포폐암에서 programmed death ligand 1 (이하 PD-L1)의 발현을 예측하는 모델을 구축해 보고자 하였다. 대상과 방법 PD-L1 발현검사 결과를 포함하고 있는 97명의 편평세포폐암 환자를 포함하였고 종양 치료 전 시행한 CT 영상 소견을 분석하였다. 전체 환자군과 40명의 진행성(≥ stage IIIB) 병기 환자군에 대하여 PD-L1 발현 예측을 위한 다중 로지스틱 회귀 분석 모델 구축을 시행하였다. 각각의 환자군에 대하여 곡선 아래 면적(areas under the receiver operating characteristic curves; 이하 AUCs)을 분석하여 예측력을 평가하였다. 결과 전체 환자군에서 '전체 유의인자 모델'(종양병기, 종양크기, 흉막결절, 폐전이)의 AUC 값은 0.652이며, '선택 유의인자 모델'(흉막결절)은 0.556이었다. 진행성 병기 환자군에서 '선택 유의인자 모델'(종양크기, 흉막결절, 폐소수전이, 간질성폐렴의 부재)의 AUC 값은 0.897이었다. 이러한 인자들 중 흉막결절과 폐소수전이는 높은 오즈비를 보였다(각각, 8.78과 16.35). 결론 본 연구에서의 모델은 편평세포폐암의 PD-L1 발현예측의 가능성을 보여주었으며 흉막결절과 폐소수전이는 PD-L1 발현을 예측하는데 중요한 CT 예측인자였다.

• 미생물학회지
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• 제49권3호
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• pp.221-227
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• 2013

인간면역결핍바이러스(Human immunodeficiency virus; HIV), B형 간염 바이러스(Hepatitis B virus; HBV), 그리고 C형 간염 바이러스(Hepatitis C virus; HCV)는 만성 감염질환을 일으키는 대표적인 바이러스들이다. 인체내 감염시 임상적 진행경과에 따른 바이러스 특이 T림프구의 항바이러스 기능변화 및 바이러스의 체내 지속성과 T림프구에 발현되는 다양한 면역인자(e.g., CD28, CD25, FoxP3, PD-1, CTLA-4)들과의 구체적인 상관관계는 최근 많은 국내외 연구진들을 통해 연구되고 있다. 그 중 FoxP3 (forkhead box P3), PD-1 (programmed death-1) 그리고 CTLA-4 (cytotoxic T lymphocyte-associated antigen 4)는 T림프구에서 발현되는 면역조절인자로 만성 바이러스성 감염시 그 발현이 증가되는 것으로 관찰되었으며, 항바이러스 작용을 가지는 T림프구의 기능결핍과 밀접한 상관관계가 있는 것으로 알려져 있다. 본 총설에서는 만성적인 HIV, HBV, 그리고 HCV 감염에서 바이러스 특이 T림프구에서 발현되는 FoxP3, PD1, 그리고 CTLA-4의 발현변화와 각 질환의 임상적 진행경과와의 상관성, 그리고 이들 발현이 T림프구의 항바이러스 기능에 미치는 영향 등을 중심으로 기술하였다.

• Journal of Gastric Cancer
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• 제23권3호
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• pp.476-486
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• 2023

Purpose: The optimal tumor mutational burden (TMB) value for predicting treatment response to programmed cell death-1 (PD-1) checkpoint inhibitors in advanced gastric cancer (AGC) remains unclear. We aimed to investigate the optimal TMB cutoff value that could predict the efficacy of PD-1 checkpoint inhibitors in AGC. Materials and Methods: Patients with AGC who received pembrolizumab or nivolumab between October 1, 2020, and July 27, 2021, at Samsung Medical Center in Korea were retrospectively analyzed. The TMB levels were measured using a next-generation sequencing assay. Based on receiver operating characteristic curve analysis, the TMB cutoff value was determined. Results: A total 53 patients were analyzed. The TMB cutoff value for predicting the overall response rate (ORR) to PD-1 checkpoint inhibitors was defined as 13.31 mutations per megabase (mt/Mb) with 56% sensitivity and 95% specificity. Based on this definition, 7 (13.2%) patients were TMB-high (TMB-H). The ORR differed between the TMB-low (TMB-L) and TMB-H (8.7% vs. 71.4%, P=0.001). The progression-free survival and overall survival (OS) for 53 patients were 1.93 (95% confidence interval [CI], 1.600-2.268) and 4.26 months (95% CI, 2.992-5.532). The median OS was longer in the TMB-H (20.8 months; 95% CI, 2.292-39.281) than in the TMB-L (3.31 months; 95% CI, 1.604-5.019; P=0.049). Conclusions: The TMB cutoff value for predicting treatment response in AGC patients who received PD-1 checkpoint inhibitor monotherapy as salvage treatment was 13.31 mt/Mb. When applying the programmed death ligand-1 status to TMB-H, patients who would benefit from PD-1 checkpoint inhibitors can be selected.