- Title
- Targeting oxidative phosphorylation for lung squamous cell carcinoma treatment
- Creator
- Xu, Ran
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2024
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Lung cancer is the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) being the predominant histological subtype. Despite advances in targeted and immune-based therapies, patients with lung squamous cell carcinoma (LUSC), a major NSCLC subtype, often face limited treatment options, underscoring the urgent need for innovative diagnostic and therapeutic strategies. Here we present a critical role for the mitochondrial protein Optic Atrophy 1 (OPA1) in facilitating mitochondrial protein synthesis, which in turn promotes oxidative phosphorylation (OXPHOS) and contributes to LUSC pathogenesis. Amplification of the distal portion of chromosome 3q, where the OPA1 gene is located, is one of the most frequent genomic alteration events in LUSC. Integrated multi-omics analyses focusing on genes within the 3q26-29 region revealed the upregulation of OPA1 in LUSC, driven by gene amplification and c-Myc-mediated transcriptional activation. By using an siRNA library targeting amplified genes within the 3q26-29 region, we identify OPA1 as a critical determinant of LUSC cell survival and proliferation. Mechanistically, OPA1 binds to Tu translation elongation factor (TUFM), facilitating its assembly to mitochondrial ribosomes and thereby promoting mitochondrial protein synthesis to enhance OXPHOS in LUSC. Furthermore, we observe a progressive increase in OPA1 expression across developmental stages of LUSC, from normal to pre-cancerous and cancerous tissues. These findings not only underscore the critical role of OPA1 in the pathogenesis of LUSC but also highlight the innovative approach of targeting OXPHOS in cancer therapy. The observation that OPA1 expression progressively escalates during the initial development of LUSC and sustains elevated levels across various stages of the disease underscores its potential utility as a longitudinal biomarker for early diagnosis and as a therapeutic target for LUSC. This study introduces a novel paradigm in the understanding of cancer metabolism, specifically linking mitochondrial protein synthesis and respiratory function to cancer cell survival and proliferation under the regulatory control of OPA1. Looking forward, further studies are needed to explore the therapeutic potential of inhibiting OPA1 in LUSC. Investigating the effects of OPA1 inhibition in combination with existing chemotherapies and immune-based therapies could provide insights into synergistic effects that may enhance treatment efficacy. Additionally, the role of OPA1 in enhancing oxidative phosphorylation should be explored in other cancers where OXPHOS plays a crucial role, to determine if the findings from LUSC can be generalised or specifically adapted for other malignancies. Long-term studies focusing on the clinical outcomes of targeting mitochondrial pathways, as well as the development of OPA1-specific inhibitors, are crucial to translating these findings into clinical applications.
- Subject
- lung cancer; non-small cell lung cancer (NSCLC); lung squamous cell carcinoma (LUSC); Optic Atrophy 1 (OPA1)
- Identifier
- http://hdl.handle.net/1959.13/1514887
- Identifier
- uon:56867
- Rights
- Copyright 2024 Ran Xu
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 4 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 163 KB | Adobe Acrobat PDF | View Details Download |