Discovery of inner centromere protein-derived small peptides for cancer imaging and treatment targeting survivin

Takeshi Fuchigami, Natsumi Ishikawa, Iori Nozaki, Yusuke Miyanari, Sakura Yoshida, Motohiro Yamauchi, Ayumi Soejima, Mamoru Haratake, Morio Nakayama

Research output: Contribution to journalArticlepeer-review

Abstract

Survivin belongs to the inhibitor of apoptosis protein family, which is consistently overexpressed in most cancer cells but rarely expressed in normal adult tissues. Therefore, the detection and inhibition of survivin are regarded as attractive strategies for cancer-specific treatment. In this study, we designed and synthesized 7-19 residues of inner centromere protein (INCENP)-derived small peptides (INC peptides) as novel survivin-targeting agents. The INC peptides showed binding affinity for the human survivin protein (Kd = 91.4-255 nmol L−1); INC16-22, which contains residues 16-22 of INCENP, showed the highest affinity (91.4 nmol L−1). Confocal fluorescence imaging showed consistent colocalization of FITC-INC16-22 and survivin in cell lines. Nona-arginine-linked INC16-22 (r9-INC16-22) rendered INC16-22 cells penetrable and strongly inhibited cell growth of MIA PaCa-2 cells (52% inhibition at 1.0 µmol L−1) and MDA-MB-231 cells (60% inhibition at 10 µmol L−1) as determined by MTT assays. The exposure of MIA PaCa-2 cells to 40 µmol L−1 r9-INC16-22 apparently reduced the intracellular protein expression levels of survivin. However, cleaved caspase-3 was significantly increased in cells treated with r9-INC16-22, even at 10 µmol L−1, compared to untreated cells. Flow cytometry revealed that r9-INC16-22 strongly induced apoptosis in MIA PaCa-2 cells. These results indicate that the cytotoxic effects of r9-INC16-22 could be mediated mainly through the disruption of survivin-dependent antiapoptotic functions and partly because of the direct degradation of the survivin protein. Our findings suggest that INC peptides can act as useful scaffolds for novel cancer imaging and anticancer agents.

Original languageEnglish
Pages (from-to)1357-1366
Number of pages10
JournalCancer Science
Volume111
Issue number4
DOIs
Publication statusPublished - Apr 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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