The CT20 peptide causes detachment and death of metastatic breast cancer cells by promoting mitochondrial aggregation and cytoskeletal disruption.
The CT20 peptide causes detachment and death of metastatic breast cancer cells by promoting mitochondrial aggregation and cytoskeletal disruption.
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DOI：
10.1038/cddis.2014.225
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发表时间：
2014-05-22
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
转移占乳腺癌死亡的大多数，推动了对可以阻止疾病进展的新疗法的需求。利用细胞生理学中癌症特异性差异合理设计的肽是一种新兴技术，有望作为转移性乳腺癌的治疗方法。我们开发了CT20 p，一种基于Bax的C末端的疏水肽，其与抗菌肽具有相似性，并且先前报道CT20 p具有独立于全长Bax的独特细胞毒性作用。在这项研究中，我们确定了CT20 p在癌细胞特异性脱离和死亡之前的细胞内作用。以前，我们发现CT20 p在癌细胞裂解物的重膜部分中迁移。在这里，使用MDA-MB-231乳腺癌细胞，我们证明了CT20 p定位于线粒体，导致融合样聚集和线粒体膜超极化。结果，CT20 p处理的MDA-MB-231细胞中线粒体的分布和运动明显受损，特别是在细胞突起中。相反，CT20 p不与正常乳腺上皮MCF-10A细胞的线粒体相关，导致线粒体膜电位、形态或定位的变化很小。在MDA-MB-231细胞中，CT20 p触发细胞脱离，在此之前α 5 β 1整合素水平降低和F-肌动蛋白聚合减少。使用叶酸靶向纳米颗粒封装并将CT20 p递送至小鼠肿瘤，我们在肽治疗的几天内实现了显著的肿瘤消退。这些结果表明，CT20 p作为癌症特异性治疗肽可用于治疗转移性疾病，其干扰线粒体形态和运动，最终导致肌动蛋白细胞骨架的破坏、细胞脱离和细胞活力的丧失。
Metastasis accounts for most deaths from breast cancer, driving the need for new therapeutics that can impede disease progression. Rationally designed peptides that take advantage of cancer-specific differences in cellular physiology are an emerging technology that offer promise as a treatment for metastatic breast cancer. We developed CT20p, a hydrophobic peptide based on the C terminus of Bax that exhibits similarities with antimicrobial peptides, and previously reported that CT20p has unique cytotoxic actions independent of full-length Bax. In this study, we identified the intracellular actions of CT20p which precede cancer cell-specific detachment and death. Previously, we found that CT20p migrated in the heavy membrane fractions of cancer cell lysates. Here, using MDA-MB-231 breast cancer cells, we demonstrated that CT20p localizes to the mitochondria, leading to fusion-like aggregation and mitochondrial membrane hyperpolarization. As a result, the distribution and movement of mitochondria in CT20p-treated MDA-MB-231 cells was markedly impaired, particularly in cell protrusions. In contrast, CT20p did not associate with the mitochondria of normal breast epithelial MCF-10A cells, causing little change in the mitochondrial membrane potential, morphology or localization. In MDA-MB-231 cells, CT20p triggered cell detachment that was preceded by decreased levels of α5β1 integrins and reduced F-actin polymerization. Using folate-targeted nanoparticles to encapsulate and deliver CT20p to murine tumors, we achieved significant tumor regression within days of peptide treatment. These results suggest that CT20p has application in the treatment of metastatic disease as a cancer-specific therapeutic peptide that perturbs mitochondrial morphology and movement ultimately culminating in disruption of the actin cytoskeleton, cell detachment, and loss of cell viability.
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DOI：
10.1523/jneurosci.1233-11.2012
发表时间：
2012-01-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Magrané J;Sahawneh MA;Przedborski S;Estévez ÁG;Manfredi G
通讯作者：
Manfredi G
影响因子：
6.2
作者：
Santra S;Perez JM
通讯作者：
Perez JM
影响因子：
1
作者：
Arismendi-Morillo, Gabriel;Hoa, Neil T.;Jadus, Martin R.
通讯作者：
Jadus, Martin R.
影响因子：
6.6
作者：
Huang, Pinwei;Yu, Tianzheng;Yoon, Yisang
通讯作者：
Yoon, Yisang
影响因子：
3.4
作者：
Garg, Pranav;Nemec, Kathleen N.;Tatulian, Suren A.
通讯作者：
Tatulian, Suren A.