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Translation Elongation Factor eEF1A2 is a Novel Anticancer Target for the Marine Natural Product Plitidepsin
Alejandro Losada1, María José Muñoz-Alonso1, Carolina García2
1Departamento de Biología Celular y Farmacogenómica, Pharma Mar S.A., Colmenar Viejo, Madrid, Spain.
Abstract:
eEF1A2 is one of the isoforms of the alpha subunit of the eukaryotic Elongation Factor 1. It is overexpressed in human tumors and is endowed with oncogenic properties, favoring tumor cell proliferation while inhibiting apoptosis. We demonstrate that plitidepsin, an antitumor agent of marine origin that has successfully completed a phase-III clinical trial for multiple myeloma, exerts its antitumor activity by targeting eEF1A2. The drug interacts with eEF1A2 with a KD of 80 nM and a target residence time of circa 9 min. This protein was also identified as capable of binding [14C]-plitidepsin in a cell lysate from K-562 tumor cells. A molecular modelling approach was used to identify a favorable binding site for plitidepsin at the interface between domains 1 and 2 of eEF1A2 in the GTP conformation. Three tumor cell lines selected for at least 100-fold more resistance to plitidepsin than their respective parental cells showed reduced levels of eEF1A2 protein. Ectopic expression of eEF1A2 in resistant cells restored the sensitivity to plitidepsin. FLIM-phasor FRET experiments demonstrated that plitidepsin localizes in tumor cells sufficiently close to eEF1A2 as to suggest the formation of drug-protein complexes in living cells. Altogether, our results strongly suggest that eEF1A2 is the primary target of plitidepsin.
Insights
The antitumor drug plitidepsin targets eukaryotic elongation factor 1 A2 (eEF1A2), a protein overexpressed in tumors. This interaction inhibits cancer cell proliferation and promotes apoptosis, highlighting eEF1A2 as a key therapeutic target.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Eukaryotic elongation factor 1 A2 (eEF1A2) is implicated in cancer progression due to its oncogenic properties.
- Plitidepsin is a marine-derived antitumor agent with demonstrated efficacy in clinical trials for multiple myeloma.
Purpose of the Study:
- To identify the molecular target of plitidepsin.
- To elucidate the mechanism by which plitidepsin exerts its antitumor effects.
Main Methods:
- Biochemical assays to determine drug-target interaction kinetics (KD, residence time).
- Cellular studies involving drug-resistant cell lines and ectopic gene expression.
- Molecular modeling to predict drug-binding site.
- Fluorescence imaging techniques (FLIM-phasor FRET) to confirm drug-target proximity in vivo.
Main Results:
- Plitidepsin binds to eEF1A2 with high affinity (KD = 80 nM) and significant residence time (~9 min).
- Reduced eEF1A2 levels correlated with plitidepsin resistance in tumor cell lines.
- Restoring eEF1A2 expression in resistant cells re-sensitized them to plitidepsin.
- In situ proximity ligation assays confirmed plitidepsin-eEF1A2 complex formation in living tumor cells.
Conclusions:
- Eukaryotic elongation factor 1 A2 (eEF1A2) is identified as the primary molecular target of plitidepsin.
- Plitidepsin's antitumor activity is mediated through its interaction with eEF1A2.
- Targeting eEF1A2 represents a promising therapeutic strategy for cancers overexpressing this protein.
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