| Author: | Yu, Yingting |
| Title: | Autophagy-targeting peptidomimetics as potent anti-proliferative therapeutic candidates against ovarian cancer |
| Advisors: | Zhao, Yan Xiang (ABCT) |
| Degree: | Ph.D. |
| Year: | 2024 |
| Subject: | Ovaries -- Cancer -- Genetic aspects Peptides Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Applied Biology and Chemical Technology |
| Pages: | xiii, 144 pages : color illustrations |
| Language: | English |
| Abstract: | Ovarian cancer, recognized as one of the most lethal gynecological malignancies, is characterized by an absence of early-stage biomarkers and efficacious therapeutic interventions, resulting in unfavorable prognoses. Predominantly, 90% of ovarian malignancies are of epithelial origin, with serous tumors accounting for 70%. These tumors are inherently heterogeneous, displaying a spectrum of clinicopathologic characteristics and behaviours attributable to their diverse tumor constituents. Consequently, the quest for potent therapeutics for ovarian cancer not only presents formidable challenges but also underscores the pressing need for expedited treatment solutions. Autophagy, a highly conserved self-degradation process in eukaryotic cells, eliminates dysfunctional cellular components via lysosome-dependent pathways. Its potential role in modulating ovarian cancer cell responses to various treatments has garnered significant interest. Some studies suggest that ovarian cancers with increased autophagy flux exhibit less aggressive symptoms and greater chemotherapeutic responsiveness. Beclin 1, a scaffold/adaptor protein, is a key regulator of autophagy, which responds to various autophagy stimuli and maintains the balance between pro-survival and pro-apoptotic processes. Our lab designed a serious of hydrocarbon stapled peptides that specifically bind to Beclin1, enhancing its interaction with UVRAG and promoting Vps34-dependent autophagy. Tat-SP4, one of the leading Beclin 1-targeting stapled peptides were further optimized by introducing new staples and residue mutations, resulting in a new generation peptide with a stronger binding affinity to Beclin 1. The leading candidate of new generation peptide, SP9, demonstrated approximately 10-fold stronger binding affinity to Beclin 1 compared to Tat-SP4 and induced autophagy with comparable efficacy. In this project, we demonstrate the anti-proliferative potency of SP9 against ovarian cancer cell lines and xenograft models, without significant toxicity. Mechanistic investigations reveal that SP9 triggers autotic cell death, along with calcium homeostasis disruption, elevated reactive oxygen species (ROS) level, mitochondria membrane potential depolarization, induction of mitochondrial permeability transition pore (mPTP) opening and defective OXPHOS activity. Autosis inhibitor digoxin can rescue SP9-induced cell death and mitigate calcium signal intervention, highlighting the crucial role of calcium in SP9-mediated cell death. Additionally, our cellular level findings suggest a synergistic effect between Beclin 1-targeting staple peptides and chemotherapy, offering reduced toxicity and enhanced anti-tumor efficacy. In summary, our optimized designed Beclin-1 targeting stapled peptides have shown potent anti-proliferative efficacy in ovarian cancer model both in vitro and in vivo, indicating that our study provides a new strategy to target autophagy for ovarian cancer treatment. Autophagy-targeting peptidomimetics exhibit potential as robust anti-tumor therapeutic candidates for use in combination with existing therapies to enhance treatment outcomes for ovarian cancer. |
| Rights: | All rights reserved |
| Access: | open access |
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