[논문]p-Coumaric acid에 의해 유도되는 인체 Jurkat T 세포의 에폽토시스 기전

이제원; 김영호

doi:10.5352/jls.2011.21.12.1678

p-Coumaric acid에 의해 유도되는 인체 Jurkat T 세포의 에폽토시스 기전
Activation of Pro-Apoptotic Multidomain Bcl-2 Family Member Bak and Mitochondria-Dependent Caspase Cascade are Involved in p-Coumaric Acid-Induced Apoptosis in Human Jurkat T Cells 원문보기

생명과학회지 = Journal of life science, v.21 no.12 = no.140, 2011년, pp.1678 - 1688

이제원 (경북대학교 자연과학대학 생명과학부) , 김영호 (경북대학교 자연과학대학 생명과학부)

초록
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다양한 식용식물에 함유되어 있는 것으로 알려진 phenolic acids의 일종인 p-coumaric acid의 항암활성을 규명하고자, 인체 급성백혈병 T 세포주인 Jurkat T 세포에 대한 p-coumaric acid의 에폽토시스 유도기전을 조사하였다. Jurkat T 세포를 p-coumaric acid (50-$150{\mu}M$)로 처리한 결과, 세포독성, 에폽토시스-관련 DNA fragmentation, 및 pro-apoptotic multidomain Bcl-2 family member인 Bak의 활성화, ${\Delta}{\psi}m$ loss, caspase-9, -3, -7, 및 -8의 활성화, 그리고 PARP 분해 등의 여러 에폽토시스-관련 생화학적 현상들이 농도의존적으로 나타났다. 그러나 이러한 에폽토시스-관련 생화학적 현상들은 Jurkat T 세포에 anti-apoptotic Bcl-2 단백질을 과발현할 경우에는 나타나지 않았다. 또한 p-coumaric acid처리에 의해 유도되는 Jurkat T 세포의 에폽토시스에는 necrosis가 수반되지 않는 것으로 확인되었다. Jurkat T 세포를 pan-caspase inhibitor인 z-VAD-fmk를 전처리할 경우, p-coumaric acid 처리에 의해 유도되는 apoptotic sub-$G_1$ peak는 차단되어 나타나지 않았으나 ${\Delta}{\psi}m$ loss는 여전히 나타났는데, 이는 p-coumaric acid처리에 의한 에폽토시스의 유도에 caspase cascade 활성화가 필수적이며 ${\Delta}{\psi}m$ loss의 downstream 현상임을 나타낸다. 한편, FADD 및 caspase-8을 함께 발현하는 Jurkat T 세포주 A3, FADD-결손 Jurkat T 세포주 I2.1, 그리고 caspase-8-결손 Jurkat T 세포주 I9.2의 p-coumaric acid의 세포독성에 대한 감수성은 서로 유사하게 나타났는데, 이는 p-coumaric acid처리에 의한 에폽토시스의 유도가 Fas와 FasL간의 상호작용에 의해 개시되지 않음을 시사한다. p-Coumaric acid의 세포독성은 Jurkat T 세포에 비해 인체 정상 말초혈액 T 세포에서 훨씬 낮게 나타났다. 이러한 결과들은 p-coumaric acid 처리에 의해 유도되는 Jurkat T 세포의 에폽토시스가 Bak 활성화, ${\Delta}{\psi}m$ loss, caspase-9, -3, -7, 및 -8로 이루어진 caspase cascade의 활성화, 그리고 PARP 분해에 의해 유도되며, 또한 anti-apoptotic 단백질인 Bcl-2의 과발현에 의해서 음성적으로 조절됨을 나타낸다.

Abstract ▼ AI-Helper

The apoptogenic effect of p-coumaric acid, a phenolic acid found in various edible plants, on human acute leukemia Jurkat T cells was investigated. Exposure of Jurkat T cells to p-coumaric acid (50-$150{\mu}M$) caused cytotoxicity and TdT-mediated dUTP nick-end labeling (TUNEL)-positive apoptotic DNA fragmentation along with Bak activation, ${\Delta}{\psi}m$ loss, activation of caspase-9, -3, -7, and -8, and PARP degradation in a dose-dependent manner. However,these apoptotic events were completely abrogated in Jurkat T cells overexpressing Bcl-2.Under these conditions, necrosis was not accompanied. Pretreatment of the cells with the pan-caspase inhibitor (z-VAD-fmk) could prevent p-coumaric acid-induced sub-$G_1$ peak representing apoptotic cells, whereas it failed to block ${\Delta}{\psi}m$ loss, indicating that the activation of caspase cascade was prerequisite for p-coumaric acid-induced apoptosis as a downstream event of ${\Delta}{\psi}m$ loss. FADD- and caspase-8-positive wild-type Jurkat T cell clone A3, FADD-deficient Jurkat T cell clone I2.1, and caspase-8-deficient Jurkat T cell clone I9.2 exhibited similar susceptibilities to the cytotoxicity of p-coumaric acid, excluding an involvement of Fas/FasL system in triggering the apoptosis. The apoptogenic activity of p-coumaric acid is more potent in malignant Jurkat T cells than in normal human peripheral T cells. Together, these results demonstrated that p-coumaric acid-induced apoptogenic activity in Jurkat T cellswas mediated by Bak activation, ${\Delta}{\psi}m$ loss, and subsequent activation of multiple caspases such as caspase-9, -3, -7, and-8, and PARP degradation, which could be regulated by anti-apoptotic protein Bcl-2.

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대상 데이터

, Shiga, Japan). FADD-positive wild-type Jurkat T cell clone A3, FADD-deficient Jurkat T cell clone I2.1, and capas-8-deficient Jurkat T cell clone I9.2 were purchased from ATCC (Manassas, VA, USA). Jurkat T cell clone transfected with vector (JT/Neo), and Jurkat T cell clone transfected with Bcl-2 gene (JT/Bcl-2) were used in this experiment.

성능/효과

Consequently, these results demonstrated that p-coumaric acid (100-150 μM) could induce apoptotic cell death in a dose-dependent manner, and confirmed that the cytotoxic effect exerted by p-coumaric acid on Jurkat T cells was mainly due to apoptosis, but not to necrosis.
In conclusion, these results demonstrate that p-coumaric acid, a naturally occurring phenolic acid found in a variety of edible plants including cereals, coffee, fruits, and vegetables, induces apoptotic DNA fragmentation of human acute T cell leukemia Jurkat cells via Bak activation, mitochondrial membrane potential (Δψm) loss, activation of caspase-9, -3, -7, and -8, and resultant cleavage of PARP.
3% at concentrations of 50 μM, 100 μM, and 150 μM p-coumaric acid, respectively. These results indicated that malignant leukemia Jurkat T cells, as compared to normal T cells, were more sensitive to the apoptogenic activity of p-coumaric acid.

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