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Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis
Maryam Aftabizadeh, … , Hua Yu, Andreas Herrmann
Maryam Aftabizadeh, … , Hua Yu, Andreas Herrmann
Published January 25, 2021
Citation Information: JCI Insight. 2021;6(2):e136176. https://doi.org/10.1172/jci.insight.136176.
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Research Article Oncology Therapeutics

Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis

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Abstract

To date, there are no inhibitors that directly and specifically target activated STAT3 and c-Myc in the clinic. Although peptide-based inhibitors can selectively block activated targets, their clinical usage is limited because of low cell penetration and/or serum stability. Here, we generated cell-penetrating acetylated (acet.) STAT3, c-Myc, and Gp130 targeting peptides by attaching phosphorothioated (PS) polymer backbone to peptides. The cell-penetrating peptides efficiently penetrated cells and inhibited activation of the intended targets and their downstream genes. Locally or systemically treating tumor-bearing mice with PS-acet.-STAT3 peptide at low concentrations effectively blocked STAT3 in vivo, resulting in significant antitumor effects in 2 human xenograft models. Moreover, PS-acet.-STAT3 peptide penetrated and activated splenic CD8+ T cells in vitro. Treating immune-competent mice bearing mouse melanoma with PS-acet.-STAT3 peptide inhibited STAT3 in tumor-infiltrating T cells, downregulating tumor-infiltrating CD4+ T regulatory cells while activating CD8+ T effector cells. Similarly, systemic injections of the cell-penetrating c-Myc and Gp130 peptides prevented pancreatic tumor growth and induced antitumor immune responses. Taken together, we have developed therapeutic peptides that effectively and specifically block challenging cancer targets, resulting in antitumor effects through both direct tumor cell killing and indirectly through antitumor immune responses.

Authors

Maryam Aftabizadeh, Yi-Jia Li, Qianqian Zhao, Chunyan Zhang, Nigus Ambaye, Jieun Song, Toshikage Nagao, Christoph Lahtz, Marwan Fakih, David K. Ann, Hua Yu, Andreas Herrmann

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Figure 1

Conjugating PS DNA oligonucleotides enables acet.-STAT3 peptide cell penetration while preserving its specific binding activity to exportin 7.

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Conjugating PS DNA oligonucleotides enables acet.-STAT3 peptide cell pen...
(A) The cell penetration efficiency (%) and fluorescence intensity of PS DNA oligonucleotide-modified STAT3 peptide (FAM labeled) in human colon cancer cell line HCT116, as assessed by flow cytometry. Data are representative of 3 independent experiments (n = 3). (B) Confirmation of the specific interaction between PS-acet.-STAT3 peptide and exportin 7 by immunoprecipitation of the FAM-labeled PS-acet.-STAT3 peptide followed by Western blotting, shown in U251 cells.
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