The Akt inhibitor ISC-4 activates prostate apoptosis response protein-4 and reduces colon tumor growth in a nude mouse model.
The Akt inhibitor ISC-4 activates prostate apoptosis response protein-4 and reduces colon tumor growth in a nude mouse model.
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DOI：
10.1158/1078-0432.ccr-10-2370
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发表时间：
2011-07-01
期刊：
影响因子：
--
通讯作者：
Irby RB
中科院分区：
文献类型：
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作者：
Sharma AK;Kline CL;Berg A;Amin S;Irby RB
前列腺凋亡反应蛋白-4(PAR-4)使细胞对化疗敏感；然而，Akt1使PAR-4失活。在此之前，我们发现过表达PAR-4的结肠癌细胞对5-FU的反应比野生型更容易。在本研究中，我们研究了Akt抑制剂苯丁基异硫氰酸酯(ISC-4)对裸鼠肿瘤生长的影响，以及PAR-4高表达细胞对野生型肿瘤生长的旁观者效应。小鼠(80只)右侧注射野生型HT29人结肠癌细胞。其中40只小鼠的左侧也注射了HT29细胞，该细胞被设计为过表达PAR-4。小鼠接受5-FU、ISC-4、其组合或赋形剂治疗。无论是否使用5-FU，ISC-4都能抑制肿瘤生长。当存在PAR-4过表达肿瘤时，野生型肿瘤比没有PAR-4过表达肿瘤时生长缓慢。在与PAR-4过表达的肿瘤生长在同一小鼠的野生型细胞中，与生长在没有PAR-4过表达的肿瘤的野生型细胞相比，PAR-4蛋白和PAR-4结合蛋白GRP78的水平增加。PAR-4过表达的肿瘤对同一小鼠体内生长的野生型肿瘤表现出旁观者效应。这表明，基因治疗不一定要达到完全渗透才能对肿瘤治疗产生积极作用。用ISC-4抑制Akt抑制肿瘤生长，对高表达PAR-4的细胞有更大的影响。数据表明，ISC-4单独或与PAR-4联合使用可以大大减少肿瘤的生长。
Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy; however, Akt1 inactivates Par-4. Previously we showed that Par-4 overexpressing colon cancer cells responded more readily to 5-FU than did wild type counterparts. In this study we investigated: 1) the effects of the Akt inhibitor, phenylbutyl isoselenocyanate (ISC-4), on tumor growth in nude mice and 2) bystander effect of Par-4 overexpressing cells on wild type tumor growth. Mice (80) were injected with wild type HT29 human colon cancer cells in the right flank. Forty of the mice were also injected in the left flank with HT29 cells engineered to overexpress Par-4. Mice were treated with 5-FU, ISC-4, a combination, or vehicle. ISC-4 reduced tumor growth, with or without 5-FU. When Par-4 overexpressing tumors were present, wild type tumors grew more slowly than when no Par-4 overexpressing tumors were present. The level of Par-4 protein as well as the Par-4 binding protein, GRP78, was increased in wild type cells growing in the same mouse as Par-4 overexpressing tumors compared to wild type tumors growing without Par-4 overexpressing tumors. Par-4 overexpressing tumors exhibited a bystander effect on wild type tumors growing distally in the same mouse. This suggests that gene therapy need not achieve total penetration to have a positive effect on tumor treatment. Inhibition of Akt with ISC-4 inhibited tumor growth and had a greater effect on cells overexpressing Par-4. The data indicate ISC-4 alone or in combination with Par-4 can greatly reduce tumor growth.