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Site-specific cholesterol depletion therapy for gastric cancer
Abstract:
Altered cholesterol metabolism is a recognized hallmark of cancer, but systemic modulation has not yet delivered significant clinical results. Accumulating evidence shows that cholesterol plays distinct roles across diverse cellular membranes, suggesting that site-specific modulation may produce superior therapeutic outcomes. Cholesterol is associated with gastric cancer (GC), but the mechanistic link is complex and no effective cholesterol-targeted therapy has been developed. Here, we report that cholesterol levels in GC cells are site-specifically elevated in the inner leaflet of the plasma membrane (IPM). This elevated IPM cholesterol constitutively activates Wnt-β-catenin signaling to drive cell survival and proliferation. Mechanistically, Niemann-Pick C1-like 1 (NPC1L1), which is highly expressed in GC patient tissues and cell lines, acts as a cholesterol flippase to raise IPM cholesterol levels, facilitating ligand-independent β-catenin signalosome formation. Ezetimibe, a clinically approved NPC1L1 inhibitor, blocks this flippase activity, lowers IPM cholesterol levels, and suppresses β-catenin signaling. Ezetimibe treatment induces apoptosis in GC cells while sparing normal primary gastric epithelial cells, which exhibit low levels of NPC1L1 and IPM cholesterol. Collectively, these results suggest that site-specific modulation of cellular cholesterol is a viable approach to developing safe and effective therapies for cancers linked to local cholesterol elevation.
Insights
Gastric cancer cells show elevated cholesterol in the inner plasma membrane, activating survival pathways. Inhibiting cholesterol transport with ezetimibe selectively kills cancer cells, offering a targeted therapy approach.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Altered cholesterol metabolism is a hallmark of cancer, but systemic therapies have yielded limited clinical success.
- Cholesterol's distinct roles in cellular membranes suggest site-specific modulation may offer therapeutic advantages.
- The link between cholesterol and gastric cancer (GC) is complex, with no effective targeted therapies developed.
Purpose of the Study:
- To investigate the site-specific role of cholesterol in gastric cancer progression.
- To identify the molecular mechanisms linking cholesterol to Wnt-β-catenin signaling in GC.
- To evaluate the therapeutic potential of targeting cholesterol metabolism in GC.
Main Methods:
- Analysis of cholesterol distribution in GC cell membranes.
- Investigating the role of Niemann-Pick C1-like 1 (NPC1L1) in cholesterol transport.
- Utilizing ezetimibe, a clinically approved NPC1L1 inhibitor, to modulate cholesterol levels.
- Assessing the impact of ezetimibe on Wnt-β-catenin signaling, cell survival, and apoptosis in GC cells and normal gastric cells.
Main Results:
- Cholesterol levels are specifically elevated in the inner leaflet of the plasma membrane (IPM) in GC cells.
- Elevated IPM cholesterol constitutively activates Wnt-β-catenin signaling, promoting GC cell survival and proliferation.
- NPC1L1, highly expressed in GC, functions as a cholesterol flippase, increasing IPM cholesterol and facilitating β-catenin signaling.
- Ezetimibe inhibits NPC1L1, reduces IPM cholesterol, suppresses β-catenin signaling, and induces apoptosis in GC cells.
- Normal gastric epithelial cells, with low NPC1L1 and IPM cholesterol, are spared by ezetimibe treatment.
Conclusions:
- Site-specific elevation of IPM cholesterol drives gastric cancer progression via Wnt-β-catenin signaling.
- NPC1L1-mediated cholesterol transport is a key mechanism in GC.
- Ezetimibe represents a promising targeted therapy for gastric cancer by selectively targeting aberrant cholesterol metabolism.
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