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Evalua&ng the An&tumor Poten&al of Chaperonin CCT modulators

22st national competition for scientific and technical research

Personalized therapy, immunotherapy and cancer

Senior Researcher : Jorge Cuellar

Research Centre or Institution : Universidad de Salamanca

Abstract

Proteostasis, or protein homeostasis, is essential for the proper functoning of eukaryotic cells, with molecular chaperones playing a crucial role in this process. Among them, the eukaryotic chaperonin CCT (chaperonin containing TCP-1) stands out for its involvement in the folding of approximately 5–10% of cellular proteins, including key cytoskeletal components such as actin and tubulin. Additionally, CCT is responsible for folding and regulating cancer-related proteins such as VHL, p53, and STAT3. Overexpression of CCT has been linked to tumor growth and metastasis, making it a promising therapeutic target for cancer treatment.

This project aims to identify pharmacological modulators of CCT and evaluate their an/tumor poten/al in cancer cell models. Through high-throughput screening of commercial compound libraries, we have identified several molecules that affect the thermal stability of CCT. Among these, five exhibit high affinity for the chaperonin, and two have demonstrated selective toxicity against breast cancer cell lines. These findings suggest that targeting CCT could be an effective strategy for combating certain types of cancer.

To validate our hypothesis, we will conduct comprehensive func/onal assays, including ATPase activity evaluation, cofactor interactions, and protein refolding studies. Additionally, we will assess critical aspects such as cell viability, cytoskeletal integrity, and migratory capacity in specific cancer cell models. These experiments will provide deeper insights into the effects of CCT modulators on tumor cells. Furthermore, we will analyze their impact on the cellular proteome using cellular thermal shift assays, offering valuable information on how these compounds influence the protein environment.

High-resolution structural characterization of CCT-modulator interactions will be performed using cutting-edge cryo-electron microscopy, allowing us to visualize these interactions at the molecular level. The expected results could lay the foundation for the development of a new generation of antitumor drugs specifically targeting CCT. This approach aims to provide more selective and effective therapeutic strategies in the fight against cancer. With this innovative strategy, we seek to contribute to cancer research advancements and improve therapeutic options for patients.

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