Analysis of survival signaling and its application for a new therapeutic strategy of cancers in gastro-intestinal tract and liver.

生存信号分析及其在胃肠道和肝癌新治疗策略中的应用。

• 批准号: 14370182
• 负责人: SASAKI Yutaka
• 金额: $ 8.45万
• 依托单位: Kumamoto University (2003-2004)Osaka University (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370182/
• 关键词: Survival signal; apoptosis; liver cancer; p38MAPK; Bcl-2 family; anti-cancer drug; Bcl-2 family; 抗がん剤; Bcl-2; 肝細胞癌; 抗癌剤; 肝癌

Different from another form of cell death called necrosis, a morphological-defined cell death, called apoptosis, has been recently observed. Apoptosis is initiated by death ligands, or by a variety of stimuli including chemotherapy, and y-irradiation.Apoptosis is strictly controlled by a variety of mechanisms at different levels. Inside the cells, the members of Bcl-2 family constitute a first class of regulatory proteins, which act at the mitochondrial level. BAD, a member of Bcl-2 family exerts its pro-apoptotic action on the mitochondrion in the non-phosphorylated state, and forms inactivating dimmers with Bel-XL or Bcl-2 to promote apoptosis. Phosphorylated BAD dissociates from the heterodimeric complex with Bel-XL or Bcl-2,restoring Bel-XL or Bcl-2 function, and activating cell survival signaling. Recent works have indicated that activated BAD kinases including Akt or PKA (A kinase) in the tumor cells play a key role in apoptosis resistance through BAD phosphorylation. We investig … More ated the involvement of intracellular survival signals in human hepatocellular carcinoma(HCC). Both Akt and PKA. were activated in HCCs compared to adjacent non-involved tissues. BAD protein was highly phosphorylated in HCCs compared to uninvolved liver. There was significant correlation between Akt or PKA activity and BAD phosphorylation in HCCs. In addition, inhibitors of these signal transduction cascade induced programmed cell death in human hepatoma cell lines. These observations indicate that survival signal suppresses programmed cell death via BAD phosphorylation in human HCCs, and suggest that it may promote escape from apoptosis to allow HCC tumor progression.On the other hand, mitogen-activated protein kinase(MAPK) cascade is activated in response to various extracellular stimuli. We examined involvement of p38 MAPK, a MAPK super family, cascade in human HCCs and hepatoma cell lines. In HCCs,MKK6,which is upstream of p38 MAPK, and p38 MAPK activities were significantly lower compared to non-tumorous lesions. There was a significant positive correlation between p38 MAPK and MKK6 activity. Moreover, there was a positive correlation between p38 MAPK and caspase-3 activity. HCCs measuring over 20 mm exhibited lower levels of MKK6 and p38 MAPK activity than did smaller tumors. MKK6 transfection increased p38 MAPK activity, cytochrome c release from the mitochondria to the cytosol, and caspase-3 activity, accompanied by apoptosis in hepatoma cell lines. In contrast, a p38 MAPK specific inhibitor prevents MKK6-induced apoptosis in hepatoma cell lines. These results indicate that the p38 MAPK cascade is consistent with induction of a programmed cell death pathway in hepatoma cells, and suggest that reduction of the p38 MAPK cascade may account, in part, for escape from apoptosis, leading to the progression of human HCC.Taking together, the modulation of activated survival signals and diminished apoptotic signals may serve as a new therapeutic strategy for cancer therapy. Less

与另一种称为坏死的细胞死亡不同，最近观察到了一种形态定义的细胞死亡，称为细胞凋亡。细胞凋亡是由死亡配体或多种刺激因素启动的，包括化疗、伽玛刀照射等，在不同水平上受到多种机制的严格控制。在细胞内，Bcl2家族的成员构成了第一类调控蛋白，作用于线粒体水平。BAD是Bcl-2家族成员之一，在非磷酸化状态下对线粒体发挥促凋亡作用，并与Bel-xl或Bcl2形成失活二聚体促进细胞凋亡。磷酸化的BAD从与Bel-xl或Bcl2的异二聚体复合体解离，恢复Bel-xl或Bcl2的功能，并激活细胞生存信号。最近的研究表明，肿瘤细胞中激活的Bad激酶，包括Akt或PKA(A Kinase)，通过BAD磷酸化在抵抗细胞凋亡中起关键作用。我们投资了…更多的是细胞内生存信号参与人肝细胞癌的发生。Akt和PKA都是。与邻近的非受累组织相比，在肝细胞癌中被激活。与未受累的肝脏相比，BAD蛋白在肝细胞癌中高度磷酸化。肝细胞中Akt和PKA活性与不良的磷酸化密切相关。此外，这些信号转导通路的抑制剂可诱导人肝癌细胞系的程序性细胞死亡。这些观察表明，生存信号通过不良的磷酸化抑制人肝癌细胞的程序性死亡，并提示它可能促进逃逸细胞凋亡以促进肝癌的进展。另一方面，丝裂原激活的蛋白激酶(MAPK)级联被激活以响应各种细胞外刺激。我们研究了p38MAPK，一个MAPK超家族，在人肝癌和肝癌细胞系中的级联作用。在肝细胞癌中，位于p38MAPK上游的MKK6和p38MAPK活性明显低于非肿瘤病变。P38MAPK与MKK6活性呈显著正相关。P38MAPK与caspase-3活性呈正相关。与较小的肿瘤相比，大于20 mm的HCCs显示出更低的MKK6和p38MAPK活性水平。MKK6基因表达上调肝癌细胞p38MAPK活性，细胞色素c从线粒体释放到胞浆，caspase-3活性增加，并伴有细胞凋亡。相反，p38 MAPK特异性抑制剂可阻止MKK6诱导的肝癌细胞系的凋亡。这些结果表明，p38MAPK级联信号通路与肝癌细胞程序性死亡通路的诱导是一致的，提示p38MAPK级联信号通路的减少可能在一定程度上是逃避细胞凋亡，导致人肝癌进展的原因之一。较少

项目成果

Housui, A., et al.: "Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon -gamma stimuli"J.Biol.Chem.. 278. 28562-28571 (2003)

Housui, A., et al.：“丙型肝炎病毒核心蛋白在白细胞介素 6 和干扰素 -gamma 刺激下不同地调节 JAK-STAT 信号通路”J.Biol.Chem.. 278. 28562-28571 (2003)

Yasumaru, M., et al.: "Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway"Cancer Res.. 63. 6726-6734 (2003)

Yasumaru, M., 等人：“抑制血管紧张素 II 活性可通过胰岛素样生长因子 I 受体途径增强环氧合酶 2 抑制剂的抗肿瘤作用”Cancer Res.. 63. 6726-6734 (2003)

Frontiers in Hepatology, HCV/Oxidative Stress and Liver Disease

肝病学、HCV/氧化应激和肝病前沿

• 发表时间: 2002
• 期刊: Hepatitis C virus core-mediated alteration of gene expression and signal transduction in the host cell(ed.K.Okita)(Springer-Verlag, Tokyo)
• 作者: Ohkawa;K.;Housui;A.;Sasaki;Y.;Hayashi;N.
• 通讯作者: N.

Gastrin enhances gastric mucosal integrity through cyclooxygenase-2 upregulation in rats

• DOI: 10.1152/ajpgi.00006.2002
• 发表时间: 2002-12-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
• 影响因子: 4.5
• 作者: Komori, M;Tsuji, S;Hori, M
• 通讯作者: Hori, M

Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway.

• DOI: 10.1016/s0016-5085(03)80280-9
• 发表时间: 2003-04
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: M. Yasumaru;S. Tsuji;M. Tsujii;T. Irie;M. Komori;A. Kimura;T. Nishida;Y. Kakiuchi;N. Kawai;H. Murata;M. Horimoto;Y. Sasaki;N. Hayashi;S. Kawano;M. Hori