Enhancement of Gemcitabine sensitivity in pancreatic adenocarcinoma by novel exosome-mediated delivery of the Survivin-T34A mutant.
Enhancement of Gemcitabine sensitivity in pancreatic adenocarcinoma by novel exosome-mediated delivery of the Survivin-T34A mutant.
复制标题
通过新型外泌体介导的Survivin-T34a突变体的递送，增强胰腺腺癌中吉西他滨敏感性的增强。
DOI：
10.3402/jev.v3.23244
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发表时间：
2014
影响因子：
16
通讯作者：
Wall NR
中科院分区：
文献类型：
--
作者：
Aspe JR;Diaz Osterman CJ;Jutzy JM;Deshields S;Whang S;Wall NR
目前晚期胰腺癌的治疗选择在很大程度上令人失望，最好的结果是中等的，虽然辅助治疗仍然存在争议，但大多数人仍然同意吉西他滨应该作为任何联合研究的一部分。凋亡抑制蛋白（IAP）Survivin是维持细胞凋亡抵抗的关键因子，其显性失活突变体（Survivin-T34 A）可阻断Survivin，诱导caspase活化和细胞凋亡。在这项研究中，将从构建为具有四环素调节的存活素-T34 A的黑素瘤细胞系收集的外来体接种在胰腺癌（MIA PaCa-2）细胞系上。评估这些外来体中生存素-T34 A的存在，然后评估它们诱导吉西他滨增强细胞杀伤的能力是这项工作的目的。在此，我们表明，在不存在四环素（tet-off）的情况下从工程化黑素瘤细胞收集的外来体确实含有存活素-T34 A，并且当单独使用或与吉西他滨组合使用时，与单独使用吉西他滨相比，在多种胰腺癌细胞系上诱导凋亡性细胞死亡的显著增加。这项exosomes/Survivin-T34 A研究表明，癌症微环境中抗癌蛋白的新递送方法可能有助于靶向胰腺癌。
Current therapeutic options for advanced pancreatic cancer have been largely disappointing with modest results at best, and though adjuvant therapy remains controversial, most remain in agreement that Gemcitabine should stand as part of any combination study. The inhibitor of apoptosis (IAP) protein Survivin is a key factor in maintaining apoptosis resistance, and its dominant-negative mutant (Survivin-T34A) has been shown to block Survivin, inducing caspase activation and apoptosis. In this study, exosomes, collected from a melanoma cell line built to harbor a tetracycline-regulated Survivin-T34A, were plated on the pancreatic adenocarcinoma (MIA PaCa-2) cell line. Evaluation of the presence of Survivin-T34A in these exosomes followed by their ability to induce Gemcitabine-potentiative cell killing was the objective of this work. Here we show that exosomes collected in the absence of tetracycline (tet-off) from the engineered melanoma cell do contain Survivin-T34A and when used alone or in combination with Gemcitabine, induced a significant increase in apoptotic cell death when compared to Gemcitabine alone on a variety of pancreatic cancer cell lines. This exosomes/Survivin-T34A study shows that a new delivery method for anticancer proteins within the cancer microenvironment may prove useful in targeting cancers of the pancreas.