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Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis
Malak Alannan1, Hala Fatrouni1, Véronique Trézéguet1
1Bordeaux Institute of Oncology (BRIC), Inserm U1312, University of Bordeaux, 33000 Bordeaux, France.
Abstract:
Deregulated lipid metabolism is a common feature of liver cancers needed to sustain tumor cell growth and survival. We aim at taking advantage of this vulnerability and rewiring the oncogenic metabolic hub by targeting the key metabolic player pro-protein convertase subtilisin/kexin type 9 (PCSK9). We assessed the effect of PCSK9 inhibition using the three hepatoma cell lines Huh6, Huh7 and HepG2 and validated the results using the zebrafish in vivo model. PCSK9 deficiency led to strong inhibition of cell proliferation in all cell lines. At the lipid metabolic level, PCSK9 inhibition was translated by an increase in intracellular neutral lipids, phospholipids and polyunsaturated fatty acids as well as a higher accumulation of lipid hydroperoxide. Molecular signaling analysis involved the disruption of the sequestome 1/Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (p62/Keap1/Nrf2) antioxidative axis, leading to ferroptosis, for which morphological features were confirmed by electron and confocal microscopies. The anti-tumoral effects of PCSK9 deficiency were validated using xenograft experiments in zebrafish. The inhibition of PCSK9 was effective in disrupting the oncometabolic process, inducing metabolic exhaustion and enhancing the vulnerability of cancer cells to iron-triggered lipid peroxidation. We provide strong evidence supporting the drug repositioning of anti-PCSK9 approaches to treat liver cancers.
Insights
Targeting pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibits liver cancer growth by disrupting lipid metabolism and inducing ferroptosis. This study supports PCSK9 inhibitors as a potential drug repositioning strategy for liver cancer treatment.
Area of Science:
- Oncology
- Metabolic pathways
- Lipid metabolism
Background:
- Deregulated lipid metabolism fuels liver cancer growth and survival.
- Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a key metabolic player in cancer.
- Targeting metabolic vulnerabilities offers a therapeutic strategy for liver cancer.
Purpose of the Study:
- To investigate the anti-tumoral effects of PCSK9 inhibition in liver cancer.
- To explore the impact of PCSK9 deficiency on cancer cell lipid metabolism and signaling pathways.
- To validate PCSK9 inhibition as a potential therapeutic approach for liver cancer.
Main Methods:
- Assessed PCSK9 inhibition effects on hepatoma cell lines (Huh6, Huh7, HepG2).
- Utilized zebrafish xenograft models for in vivo validation.
- Analyzed lipid profiles, lipid peroxidation, and the p62/Keap1/Nrf2 antioxidative axis.
- Confirmed ferroptosis induction via electron and confocal microscopy.
Main Results:
- PCSK9 deficiency significantly inhibited proliferation in all tested hepatoma cell lines.
- PCSK9 inhibition increased intracellular neutral lipids, phospholipids, polyunsaturated fatty acids, and lipid hydroperoxide.
- Disruption of the p62/Keap1/Nrf2 axis led to ferroptosis, confirmed by morphological analysis.
- Zebrafish xenografts demonstrated anti-tumoral effects of PCSK9 deficiency.
Conclusions:
- PCSK9 inhibition disrupts the oncometabolic process in liver cancer cells.
- Targeting PCSK9 induces metabolic exhaustion and enhances cancer cell susceptibility to ferroptosis.
- Anti-PCSK9 strategies show promise for drug repositioning in liver cancer treatment.
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