Chaperonin Containing-TCP-1 Protein Level in Breast Cancer Cells Predicts Therapeutic Application of a Cytotoxic Peptide
| Autor: | Charalambos Kaittanis, Kathleen N. Nemec, Robert W. Sprung, Rania Bassiouni, Priya Vishnubhotla, Amr S. Khaled, Annette R. Khaled, Anne Showalter, Jesus Manuel Perez, Orielyz Flores, Ashley Iketani |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology medicine.medical_specialty Cell Survival Polymers Antineoplastic Agents Breast Neoplasms Biology Article 03 medical and health sciences 0302 clinical medicine Breast cancer Cell Movement Cell Line Tumor medicine Cell Adhesion Cytotoxic T cell Humans Cell adhesion Cytotoxicity Tissue microarray Cell migration medicine.disease Prognosis Gene Expression Regulation Neoplastic Protein Subunits 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research Nanoparticles Female Peptides Intracellular Chaperonin Containing TCP-1 Protein Binding |
| Popis: | Purpose: Metastatic disease is a leading cause of death for patients with breast cancer, driving the need for new therapies. CT20p is a peptide previously discovered by our group that displays cancer-specific cytotoxicity. To design the optimal therapeutic use of the peptide, we identified the intracellular target of CT20p in breast cancer cells, correlating expression patterns of the target with susceptibility to CT20p. Experimental Design: Using polymeric nanoparticles to deliver CT20p, we assessed cytoskeletal changes, cell migration, adhesion, and viability in cells treated with the peptide. Protein pull-down experiments, coupled to mass spectrometry, enabled identification of the peptide's intracellular target. Biochemical and histologic techniques validated target identity in human cell lines and breast cancer tissue microarrays and revealed susceptibility patterns to CT20p. Results: Chaperonin containing TCP-1 (CCT) was identified as the intracellular target of CT20p. Cancer cells susceptible to CT20p had increased CCT, and overexpression of CCTβ, a subunit of the CCT complex, enhanced susceptibility to CT20p. Susceptible cells displayed reduced tubulin, a substrate of CCT, and inhibition of migration upon CT20p treatment. CCTβ levels were higher in invasive ductal carcinomas than in cancer adjacent tissues and increased with breast cancer stage. Decreased breast cancer patient survival correlated with genomic alternations in CCTβ and higher levels of the chaperone. Conclusions: Increased CCT protein in breast cancer cells underlies the cytotoxicity of CT20p. CCT is thus a potential target for therapeutic intervention and serves as a companion diagnostic to personalize the therapeutic use of CT20p for breast cancer treatment. Clin Cancer Res; 22(17); 4366–79. ©2016 AACR. |
| Databáze: | OpenAIRE |
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