Enhancing Radioiodide uptake by modulating NIS Endocytosis and degradation pathways

Zha, Ling ORCID: 0009-0000-8964-6614 (2025). Enhancing Radioiodide uptake by modulating NIS Endocytosis and degradation pathways. University of Birmingham. Ph.D.

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Abstract

The effectiveness of radioiodide therapy for differentiated thyroid cancer is often compromised by the mislocalisation of the sodium/iodide symporter (NIS) away from the plasma membrane, as well as its dysregulated expression. While increasing NIS expression has been the focus of previous and on-going studies, mislocalisation remains a significant barrier. This thesis investigates aspects of the post-translational processing of NIS, identifying critical therapeutic opportunities to enhance its function.

Key NIS interactors, including the AP2 adaptor complex, PBF, moesin, and VCP, were explored for their potential roles in NIS endocytosis and trafficking. This revealed that disrupting specific motifs within the NIS C-terminus, particularly the diacidic and dileucine motifs, significantly impacts NIS localisation and function. The efficacy of the specific VCP inhibitors CB-5083 and CB-5339 was appraised in breast cancer cell lines, demonstrating an increase in radioiodide uptake at specific concentrations. However, the effects were not NIS-mediated in all cases. Structural analogues of clotrimazole and NMS-873 were also developed to address bioavailability challenges, demonstrating modest improvements in radioiodide uptake and providing an alternative strategy to modulate NIS degradation. Additionally, the critical impact of NIS dimerisation on its function and trafficking was investigated. Mutations at key residues within the dimerisation interface, particularly K554 and R555, were found to impair NIS dimerisation, reduce iodide uptake, and affect NIS protein expression and localisation.

Thus, new insights into NIS subcellular localisation, processing, function and pharmacological modulation were derived, allowing new strategic approaches to enhancing radioiodide uptake in thyroid cancer to be identified.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):