Anticancer Activity and Mechanism of Action of kla-TAT Peptide
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Anticancer Activity and Mechanism of Action of kla‑TAT Peptide Xiaolong Chen1,2 · Cuihua Hu3,4 · Yanan Zhang1,2 · Wenjing Hao1,2 · Xu He1,2 · Qing Li1,2 · Yuxi Huang3,4 · Yibing Huang1,2 · Yuxin Chen1,2,5 Accepted: 7 January 2020 © Springer Nature B.V. 2020
Abstract Conjugation of cell-penetrating peptides to anticancer peptides is an effective strategy to enhance tumor treatment. The hybrid peptide, kla-TAT, by attaching the TAT peptide to the C-terminus of the pro-apoptotic peptide kla exhibited strong anticancer activity when co-administration with other peptide, but the systematic mechanism was not clear. In this study, the mechanisms of action of kla-TAT including the uptake pathway, distribution in cytoplasm, apoptosis-inducing ability and micro-morphology were investigated. The results indicated that the hybrid peptide internalized into A549 cells through two transmembrane mechanisms: endocytosis mediated by the clathrin-mediated endocytosis route and the rapid membrane disruption mechanism. Peptides that were endocytosed could interact with the mitochondrial membrane, while peptides internalized by disrupting the cell membrane caused disruption of the mitochondrial membrane. Thus, the hybrid kla-TAT peptide transfers through the cell membrane, inducing apoptosis by destroying the mitochondrial membrane and causethe expression of cyclin-D1 down-regulation. Meanwhile, the changes of the micro-morphology of the cancer cells was detected using atomic force microscope (AFM) and scanning electron microscope (SEM), which provided the visualized evidence for the mechanism of the peptides. Keywords Conjugation · Proapoptotic peptide · Cell penetrating peptide · Endocytosis · AFM
Introduction Xiaolong Chen, Cuihua Hu and Yanan Zhang contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10989-020-10019-5) contains supplementary material, which is available to authorized users. * Yuxin Chen [email protected] 1
Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, 2699 Qianjin St., Changchun 130021, China
2
School of Life Sciences, Jilin University, Changchun 130021, China
3
Ministry of Education Key Laboratory for Cross‑Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
4
International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
5
Jiangsu ProteLight Pharmaceutical & Biotechnology Co., Ltd, Jiangyin 214437, China
Human cancer is still a major cause of high morbidity and mortality, affecting millions of people, and there is an urgent need to develop new, selective and more efficient drugs (Ferlay et al. 2010; Gaspar et al. 2013). Apoptosis, or programmed cell death, is one of the major pathways of cancer cell death (Hassan et al. 2014). The mitochondria-mediated apoptosis pathway is a major apoptotic pathway involving
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