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Exosomal Survivin-T34A: A Novel, Potential Cancer Therapeutic.

机译：外体生存素-T34A：一种新型的潜在癌症治疗方法。

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摘要

Pancreatic cancer is the fourth most common cause of cancer fatality in American men and women with a less than 5% survival rate. Currently, if diagnosed early, surgical resection remains the only viable cure. However, only 20% of pancreatic cancer patients meet these criteria. It is therefore necessary to discover new therapies or therapeutic combinations in order to impact significantly this deadly disease. The anti-metabolite agent Gemcitabine is currently being employed to treat pancreatic cancer. While Gemcitabine has shown significant benefit in clinical applications, its ability to more than modestly impact pancreatic cancer is limited. It has been speculated that combinatory treatments using Gemcitabine could improve survival rates. Survivin, a member of the inhibitor of apoptosis (IAP) protein family, is expressed in virtually all cancer cells, but not detectable in most normal cells outside of development. Mutation of Survivin's Threonine 34 to Alanine (Survivin-T34A) abolishes a phosphorylation site for p34cdc2-cyclin B1 resulting in the initiation of the mitochondrial apoptotic pathway in cancer cells with little to no direct effects on normal cells. The possibility that targeting Survivin in this manner may provide a novel approach for selective cancer gene therapy has yet to be fully evaluated. We have recently described that cells generated to express a stable form of the mutant protein, released this Survivin-T34A to the conditioned medium. When this conditioned medium was collected and deposited on naive tumor cells, conditioned medium containing Survivin-T34A was as effective as chemotherapy in induction of tumor cell apoptosis. When combined with other forms of genotoxic stress, Survivin-T34A potentiated their killing effects. We further determined that Survivin-T34A is trafficked by microvesicles called exosomes, which are released into the conditioned media. We showed strong evidence that exosomes containing Survivin-T34A elicited cellular death and synergistically enhanced cellular death during combination with low doses of Gemcitabine and we propose that these findings may lead to novel modalities for cancer therapies. This dissertation provides the rational for Survivin-T34A's potential as a therapeutic. Next, we provide evidence that extracellular Survivin-T34A can elicit its anti-tumor effects on treated cells. Finally, I show that extracellular Survivin-T34A is found in exosomes.
机译：在美国男性和女性中，胰腺癌是癌症死亡的第四大最常见原因，其存活率低于5％。目前，如果尽早诊断，手术切除仍是唯一可行的治疗方法。但是，只有20％的胰腺癌患者符合这些标准。因此，有必要发现新的疗法或治疗组合以显着影响这种致命疾病。抗代谢药物吉西他滨目前被用于治疗胰腺癌。尽管吉西他滨在临床应用中显示出显着的优势，但其对胰腺癌的影响不大。据推测，吉西他滨联合治疗可提高生存率。 Survivin是凋亡（IAP）蛋白质抑制剂的成员，实际上在所有癌细胞中都有表达，但在发育以外的大多数正常细胞中均未检测到。 Survivin的苏氨酸34突变为丙氨酸（Survivin-T34A）消除了p34cdc2-cyclin B1的磷酸化位点，导致癌细胞中线粒体凋亡途径的启动，而对正常细胞几乎没有直接影响。以这种方式靶向Survivin可能为选择性癌症基因治疗提供新方法的可能性尚未得到充分评估。我们最近描述了产生表达稳定形式的突变蛋白的细胞，将这种Survivin-T34A释放到条件培养基中。当收集该条件培养基并将其沉积在幼稚肿瘤细胞上时，含有Survivin-T34A的条件培养基在诱导肿瘤细胞凋亡方面与化学疗法一样有效。当与其他形式的遗传毒性应激结合时，Survivin-T34A增强了其杀伤作用。我们进一步确定Survivin-T34A被称为外泌体的微泡运输，该微泡被释放到条件培养基中。我们显示有力的证据表明，与低剂量吉西他滨联用时，含有Survivin-T34A的外泌体引起细胞死亡并协同增强细胞死亡，我们建议这些发现可能会导致癌症治疗的新方法。本文为Survivin-T34A作为治疗药物的潜力提供了理论依据。接下来，我们提供证据表明细胞外Survivin-T34A可以引起其对治疗细胞的抗肿瘤作用。最后，我证明在外泌体中发现了细胞外Survivin-T34A。

著录项

  • 作者

    Aspe, Jonathan Richard.;

  • 作者单位

    Loma Linda University.;

  • 授予单位 Loma Linda University.;
  • 学科 Chemistry Biochemistry.;Health Sciences Oncology.;Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 118 p.
  • 总页数 118
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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