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Thermal Proteome Profiling Reveals Insight to Antiproliferative and Pro-Apoptotic Effects of Lagunamide A in the
Yudong Hu1, Dietrich Mostert2, Christina Orgler1
1Department of Pharmacy, Ludwig-Maximilians-University, Butenandtstr. 5, 81377, Munich, Germany.
Abstract:
Lagunamide A is a biologically active natural product with a yet unidentified molecular mode of action. Cellular studies revealed that lagunamide A is a potent inhibitor of cancer cell proliferation, promotes apoptosis and causes mitochondrial dysfunction. To decipher the cellular mechanism responsible for these effects, we utilized thermal protein profiling (TPP) and identified EYA3 as a stabilized protein in cells upon lagunamide A treatment. EYA3, involved in the DNA damage repair process, was functionally investigated via siRNA based knockdown studies and corresponding effects of lagunamide A on DNA repair were confirmed. Furthermore, we showed that lagunamide A sensitized tumor cells to treatment with the drug doxorubicin highlighting a putative therapeutic strategy.
Insights
Lagunamide A inhibits cancer cell proliferation by stabilizing EYA3, a protein crucial for DNA repair. This discovery suggests a potential therapeutic strategy for cancer treatment.
Area of Science:
- Natural Products
- Molecular Biology
- Cancer Research
Background:
- Lagunamide A is a natural product with demonstrated anticancer properties.
- Its precise molecular mechanism of action remains largely unknown.
- Observed effects include inhibition of cancer cell proliferation, apoptosis induction, and mitochondrial dysfunction.
Purpose of the Study:
- To elucidate the molecular targets and cellular mechanisms of Lagunamide A.
- To identify proteins whose stability is affected by Lagunamide A treatment.
- To investigate the role of identified targets in Lagunamide A's biological effects.
Main Methods:
- Thermal protein profiling (TPP) was employed to identify proteins stabilized by Lagunamide A.
- siRNA-based knockdown studies were performed to functionally assess the role of the identified protein.
- Cellular assays were conducted to confirm effects on DNA repair and drug sensitization.
Main Results:
- TPP identified EYA3 (eyes absent homolog 3) as a protein stabilized by Lagunamide A.
- EYA3 plays a role in DNA damage repair pathways.
- Lagunamide A treatment was confirmed to impact DNA repair processes.
- Lagunamide A sensitized tumor cells to doxorubicin treatment.
Conclusions:
- Lagunamide A's mechanism involves the stabilization of EYA3, impacting DNA repair.
- This interaction highlights a potential therapeutic strategy combining Lagunamide A with DNA-damaging agents like doxorubicin.
- Further research into EYA3 modulation could yield novel cancer therapies.
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