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Discovery of inner centromere protein-derived small peptides for cancer imaging and treatment targeting survivin
Takeshi Fuchigami1, Natsumi Ishikawa1, Iori Nozaki1
1Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
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.
Insights
Novel inner centromere protein (INC) peptides target and inhibit survivin, a protein overexpressed in cancer. The peptide r9-INC16-22 effectively induces apoptosis and inhibits cancer cell growth, offering potential for new cancer treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Survivin, an inhibitor of apoptosis protein, is overexpressed in most cancers, making it a target for cancer-specific therapies.
- Developing novel agents to detect and inhibit survivin is crucial for advancing cancer treatment strategies.
Purpose of the Study:
- To design and synthesize small peptides derived from inner centromere protein (INCENP) as novel survivin-targeting agents.
- To evaluate the binding affinity, cellular uptake, and anticancer efficacy of these INC peptides.
Main Methods:
- Synthesis of 7-19 residue INCENP-derived peptides (INC peptides).
- Assessing binding affinity to human survivin protein using Kd measurements.
- Confocal fluorescence imaging to confirm colocalization with survivin.
- Evaluating cell growth inhibition via MTT assays and apoptosis induction using flow cytometry.
- Measuring intracellular survivin levels and cleaved caspase-3 expression.
Main Results:
- INC peptides demonstrated binding affinity for human survivin, with INC16-22 showing the highest affinity (Kd = 91.4 nmol L-1).
- Nona-arginine-linked INC16-22 (r9-INC16-22) enhanced cellular penetration and significantly inhibited the growth of MIA PaCa-2 and MDA-MB-231 cancer cells.
- r9-INC16-22 treatment reduced intracellular survivin levels, increased cleaved caspase-3, and strongly induced apoptosis in MIA PaCa-2 cells.
Conclusions:
- The cytotoxic effects of r9-INC16-22 are primarily mediated by disrupting survivin's antiapoptotic functions and partly by direct survivin degradation.
- INC peptides serve as promising scaffolds for developing novel cancer imaging agents and anticancer therapeutics.
- Targeting survivin with INC peptides represents a viable strategy for developing new cancer treatments.
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