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Cell‐penetrating and endoplasmic reticulum‐locating TAT‐IL‐24‐KDEL fusion protein induces tumor apoptosis
Author(s) -
Zhang Jian,
Sun Aiyou,
Xu Rui,
Tao Xinyi,
Dong Yuguo,
Lv Xinxin,
Wei Dongzhi
Publication year - 2016
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25054
Subject(s) - endoplasmic reticulum , kdel , microbiology and biotechnology , apoptosis , fusion protein , stim1 , chemistry , biology , golgi apparatus , biochemistry , gene , recombinant dna
Interleukin‐24 (IL‐24) is a unique IL‐10 family cytokine that could selectively induce apoptosis in cancer cells without harming normal cells. Previous research demonstrated that intracellular IL‐24 protein induces an endoplasmic reticulum (ER) stress response only in cancer cells, culminating in apoptosis. In this study, we developed a novel recombinant fusion protein to penetrate into cancer cells and locate on ER. It is composed of three distinct functional domains, IL‐24, and the targeting domain of transactivator of transcription (TAT) and an ER retention four‐peptide sequence KDEL (Lys‐Asp‐Glu‐Leu) that link at its NH 2 and COOH terminal, respectively. The in vitro results indicated that TAT‐IL‐24‐KDEL inhibited growth in bladder cancer cells, as well as in non‐small cell lung cancer cell line and breast cancer cell line, but the normal human lung fibroblast cell line was not affected, indicating the cancer specificity of TAT‐IL‐24‐KDEL. Western blot analysis showed that apoptosis activation was induced by TAT‐IL‐24‐KDEL through the ER stress‐mediated cell death pathway. Treatment with TAT‐IL‐24‐KDEL significantly inhibited the growth of human H460 xenografts in nude mice, and the tumor growth inhibition was correlated with increased hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL) staining. These findings suggest that the artificially designed recombinant fusion protein TAT‐IL‐24‐KDEL may be highly effective in cancer therapy and worthy of further evaluation and development. J. Cell. Physiol. 230: 84–93, 2016. © 2015 Wiley Periodicals, Inc.