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RISS 인기검색어
- 검색키워드
- 주제어 : Renca (검색결과 4 건)
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Lee, Myungyeon 가천대학교 대학원 2017 국내석사
Compound C is a cell-permeable pyrazolopyrimidine derivative that is known as an inhibitor of AMP-activated protein kinase (AMPK). Previously, we reported that Compound C reduced the cell viability in human diploid fibroblasts and other platelet-derived growth factor (PDGF) receptor-expressing cells via its inhibitory effects on PDGF-induced signal transduction and cell proliferation in an AMPK-independent manner. We also observed that Compound C reduced the cell viability of Renca murine renal epithelial carcinoma cells, as judged by MTT assay. Therefore, the molecular mechanism of its anti-proliferative effect was investigated in Renca cells. Flow cytometric analysis revealed that Compound C arrested Renca cells in the G2/M phase of the cell cycle. Although Compound C pretreatment reduced serum-dependent phosphorylation of PDGF receptor and Akt, it increased ERK1/2 activation and reactive oxygen species (ROS) production at the early time points. Although pretreatment with N-acetyl cysteine (NAC), one of ROS scavengers, reduced Compound C-induced G2/M cell cycle arrest and recovered cell viability, its effects were very weak. There might be additional factors to explain the mechanism of Compound C-induced G2/M arrest. Although the levels of some cell cycle regulatory proteins, such as phosphorylated pRB, Cdks and cyclins, were not significantly altered by long-term treatment with Compound C, it increased the level of phospho-Tyr15-Cdc2 and decreased the level of phospho-Ser10-histone H3 at 16-24 h. Because activation of Cdc2 and subsequent phosphorylation of histone H3 are obligate steps for entry into mitosis, Compound C-induced increase in inhibitory tyrosine phosphorylation of Cdc2 and decrease in the level of P-Ser10-histone H3 might be responsible, at least in part, for G2/M cell cycle arrest. Compound C also reduced Renca cells adhesion and invasion/migration, as shown in the in vitro cell systems. The effect of Compound C on tumor growth in the syngeneic mouse model was also investigated. As expected, Compound C significantly inhibited the growth of Renca xenografts in the syngeneic Balb/c mice. Inhibition of tumor growth may be attributed mainly to reduced cell proliferation via G2/M cell cycle arrest and in part to decreased cell adhesion and migration/invasion in Compound C-treated mice. These findings suggest the potential use of Compound C against tumor development and progression.
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항 종양 면역치료에서 CD137분자의 역할 : The Role of CD137 in anti-tumor immunotherapy.
Renal cell carcinoma (RCC), one of the most incurable malignancies, is highly resistant to chemotherapy and radiotherapy. Cytokine immunotherapy has been the standard approach, but the overall response rate is still very low. Administration of agonistic anti-4-1BB monoclonal antibody (mAb) has been shown to induce regression of several animal tumors but its effect on RCC is unknown. We show here that monotherapy with either anti-4-1BB mAb or the cytotoxic drug, 5-fluorouracil (5-FU), has little effect on established RCC, Renca tumors, but combination therapy with anti-4-1BB mAb and 5-FU eradicates the tumors in more than 70 % of mice. The regressing tumor tissues from mice receiving the combination therapy contained more apoptotic tumor cells and tumor infiltrating lymphocytes than tumor tissues from mice receiving 5-FU or anti-4-1BB mAb monotherapy. The number of lymphocytes in the spleens and tumor- draining lymph nodes (TDLNs) of the combination therapy mice was greatly increased compared to that of control or 5-FU monotherapy mice. Mice that had recovered due to the combination therapy rapidly rejected rechallenge with the tumor, pointing to the establishment of long-lasting tumor-specific memory. Our results indicate that targeting tumors with 5-FU, and immune cells with 4-1BB stimulation, could be a useful strategy for treating incurable RCC. CD137 (4-1BB) is an important costimulatory receptor that is expressed by activated natural killer (NK) cells, T cells, and DCs. It has been reported that administration of agonistic anti-4-1BB mAb produce regression of established tumors in animal models. Surprisingly, we found that 4-1BB deficient mice (4-1BB-/-) could also regress established tumors. In this study, we subcutaneously injected CT26 colon carcinoma, RENCA renal cell carcinoma and EL4 lymphom to 4-1BB-/- or 4-1BB+/+ littermate mice. Initial tumor growth rates were the same between two groups of mice. However, in 10-20 days after tumor inoculation, tumors in 4-1BB-/- mice were spontaneously regressed, while tumors in 4-1BB+/+ mice continuously grew. Phenotypic analysis of leukocytes revealed tumor-rejecting 4-1BB-/- mice have higher numbers of CD8+ lymphocytes and tumor-cell specific cytolytic cell activities than tumor-bearing 4-1BB+/+ mice have. Selective depletion of CD8 cells in mice, 4-1BB-/- mice resulted in completely abrogated antitumor effect. In addition, in the tumor bearing-4-1BB-/- mice, inflammatory cytokines including IFN- , TNF- , IL-6, and MCP-1 were increased dramatically in the tumor tissues compared with the levels in the 4-1BB+/+ mice. Our results provided evidence that the lack of 4-1BB in immune cells resulted in spontaneous regression of tumor growth accompanied with environment to enhance CD8+ T celll proliferation and maintaine inflammatory environment, it may lead to antitumor immunity inside the tumor.
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CD137과 TLR신호전달에 의한 T-세포 활성화 기작연구
4-1BB는 TNFR superfamily member에 속하는 공동자극 분자로써 항원 자극 후, CD8 T 세포의 표면에 유도된다. 항진성 4-1BB 단일 클론 항체 투여에 의해 4-1BB를 자극하면 항암면역반응이 증진되어 종양의 크기를 감소시키는 것으로 알려져 있다. 그러나 4-1BB에 의해 종양을 완전히 치료할 수 있는 종양은 극히 한정되어 있어 4-1BB의 항암면역반응을 상승시킬 다른 요인이 필요하다. TLR은 병원체를 인지하는 분자로 TLR 신호는 여러 면역세포를 활성화시킨다. 본 연구에서는 항진성 4-1BB 단일 클론 항체 투여로 사람의 말초혈액에서 분리한 PBMC와 CD8 T-세포의 수가 상당하게 증가하는 것을 발견하였다. 4-1BB와 TLR2 ligand가 사람 PBMC cell의 proliferation을 증가시킨다는 결과를 얻었고, PBMC에서 분리한 CD8+cell 에서도 같은 양상을 확인하였다. 또한 a-hCD3와 4-1BB로 자극을 준 CD8+ human T-cell에서 TLR2 expression이 증가함을 확인하였다. 그리고 이와 동일한 현상을 mouse에서 4-1BB와 TLR2 동시 자극으로 면역세포를 활성화시켜 항암면역반응을 극대화시키고자 하였다. Mice에 Renca tumor cell을 주사하여 4-1BB와 TLR ligand의 공동자극에 의해 mouse들의 tumor size가 상당히 감소하는 현상을 확인하였고 wild mouse에서 4-1BB와 TLR2 ligand공동자극에 의해 CD8+T-cell이 증식하는 것을 확인한 것에 반해 TLR2가 결여된 mice로부터 분리한 CD8+ T세포에서 4-1BB와 TLR2의 공동자극에 의한 synergistic한 효과가 관찰되지 않았다. 본 연구는 4-1BB와 TLR2를 동시 자극하여 난치성 종양을 면역치료할 수 있는 가능성을 나타낸다.
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