Lipid-Raft-Targeted Molecular Self-Assembly Inactivates YAP to Treat Ovarian Cancer
Guanying Li1, Xunwu Hu1, Pingping Nie2,3
1Bioinspired Soft Matter Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan.
Abstract:
The Yes-associated protein (YAP) is a major oncoprotein responsible for cell proliferation control. YAP's oncogenic activity is regulated by both the Hippo kinase cascade and uniquely by a mechanical-force-induced actin remodeling process. Inspired by reports that ovarian cancer cells specifically accumulate the phosphatase protein ALPP on lipid rafts that physically link to actin cytoskeleton, we developed a molecular self-assembly (MSA) technology that selectively halts cancer cell proliferation by inactivating YAP. We designed a ruthenium-complex-peptide precursor molecule that, upon cleavage of phosphate groups, undergoes self-assembly to form nanostructures specifically on lipid rafts of ovarian cancer cells. The MSAs exert potent, cancer-cell-specific antiproliferative effects in multiple cancer cell lines and in mouse xenograft tumor models. Our work illustrates how basic biochemical insights can be exploited as the basis for a nanobiointerface fabrication technology which links nanoscale protein activities at specific subcellular locations to molecular biological activities to suppress cancer cell proliferation.
Insights
Researchers developed a novel molecular self-assembly technology to halt cancer cell proliferation by targeting the Yes-associated protein (YAP) oncoprotein. This innovative approach shows promise for specific ovarian cancer therapies.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- The Yes-associated protein (YAP) is a key oncoprotein regulating cell proliferation.
- YAP activity is influenced by the Hippo kinase cascade and mechanical-force-induced actin remodeling.
- Ovarian cancer cells exhibit specific accumulation of alkaline phosphatase (ALPP) on lipid rafts linked to the actin cytoskeleton.
Purpose of the Study:
- To develop a molecular self-assembly (MSA) technology for selectively inactivating YAP and halting cancer cell proliferation.
- To leverage insights into ovarian cancer cell biology for targeted cancer therapy.
Main Methods:
- Designed a ruthenium-complex-peptide precursor molecule for self-assembly.
- Developed MSAs that self-assemble on lipid rafts of ovarian cancer cells upon phosphate group cleavage.
- Investigated the antiproliferative effects in various cancer cell lines and mouse xenograft models.
Main Results:
- The developed MSAs selectively target lipid rafts on ovarian cancer cells.
- MSAs demonstrated potent, cancer-cell-specific antiproliferative effects.
- Successful suppression of cancer cell proliferation in both in vitro and in vivo models.
Conclusions:
- Molecular self-assembly technology can be effectively used to target and inactivate YAP, a key oncoprotein.
- This approach offers a novel strategy for developing targeted cancer therapies, particularly for ovarian cancer.
- The study highlights the potential of nanobiointerface fabrication for linking subcellular activities to therapeutic outcomes.
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