Thesis
The Role of CLU in Platinum-Based Drug-Resistant Ovarian Cancer
Honours, Murdoch University
2025
Abstract
High-grade serous ovarian carcinoma (HGSOC) remains a leading cause of cancer death among women. Unfortunately, most patients are not responsive or become resistant to the primary treatment, platinum-based chemotherapy. Poor response to platinum-based chemotherapy has previously been linked to overexpression of CLU (clusterin) in HGSOC. Here, we used small interfering RNAs to investigate the role of CLU in mediating the sensitivity of platinum-treated HGSOC. We found that decreased CLU led to increased resistance in HGSOC cell lines, OVCA-432 and OVCAR-3, contradicting previous studies. Western blotting confirmed the knockdown of CLU, with three protein bands (~40, ~60, and >100 kDa) affected. The ~60 kDa band corresponds to the expected molecular weight of the pre-secreted isoform, and the ~40 kDa band corresponds to the mature secreted form. Interestingly, the secreted isoform has been proposed to be anti-apoptotic; however, in our experiments, we observed increased cell survival when CLU was silenced. Our results suggest a re-evaluation of CLU’s role in platinum-resistant HGSOC. It also casts doubt on the antisense oligonucleotide drug, OGX-011, targeting secreted CLU mRNA, which was proposed to increase sensitivity to chemotherapy. Notably, the validity of the publications relating to OGX-011 has recently been drawn into question. We have shown that reducing CLU in HGSOC decreases sensitivity to platinum-based chemotherapy. In follow-up experiments, we plan to transiently express CLU isoforms with plasmids in the SKOV-3 (CLU-deficient ovarian cancer cells) to see if overexpression of CLU increases platinum sensitivity.
Details
- Title
- The Role of CLU in Platinum-Based Drug-Resistant Ovarian Cancer
- Authors/Creators
- Jess Scott
- Contributors
- Alistair R.R. Forrest (Supervisor) - Harry Perkins Institute of Medical ResearchWeitao Lin (Supervisor)Kim Rice (Supervisor) - Murdoch University, School of Medical, Molecular and Forensic Sciences
- Awarding Institution
- Murdoch University; Honours
- Identifiers
- 991005845957907891
- Murdoch Affiliation
- Murdoch University
- Resource Type
- Thesis
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