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British Journal of Cancer Nov 2018Through several not-fully-characterised moonlighting functions, translation elongation factor eEF1A2 is known to provide a fitness boost to cancer cells. Furthermore,...
BACKGROUND
Through several not-fully-characterised moonlighting functions, translation elongation factor eEF1A2 is known to provide a fitness boost to cancer cells. Furthermore, eEF1A2 has been demonstrated to confer neoplastic characteristics on preneoplastic, nontumourigenic precursor cells. We have previously shown that eEF1A2 is the target of plitidepsin, a marine drug currently in development for cancer treatment. Herein, we characterised a new signalling pathway through which eEF1A2 promotes tumour cell survival.
METHODS
Previously unknown binding partners of eEF1A2 were identified through co-immunoprecipitation, high-performance liquid chromatography-mass spectrometry and proximity ligation assay. Using plitidepsin to release eEF1A2 from those protein complexes, their effects on cancer cell survival were analysed in vitro.
RESULTS
We uncovered that double-stranded RNA-activated protein kinase (PKR) is a novel eEF1A2-interacting partner whose pro-apoptotic effect is hindered by the translation factor, most likely through sequestration and inhibition of its kinase activity. Targeting eEF1A2 with plitidepsin releases PKR from the complex, facilitating its activation and triggering a mitogen-activated protein kinase signalling cascade together with a nuclear factor-κB-dependent activation of the extrinsic apoptotic pathway, which lead to tumour cell death.
CONCLUSIONS
Through its binding to PKR, eEF1A2 provides a survival boost to cancer cells, constituting an Achilles heel that can be exploited in anticancer therapy.
Topics: Animals; Cell Survival; HeLa Cells; Humans; Mice; NF-kappa B; Peptide Elongation Factor 1; Protein Binding; Signal Transduction; eIF-2 Kinase
PubMed: 30420615
DOI: 10.1038/s41416-018-0336-y -
Annals of Oncology : Official Journal... Jul 2015Preclinical data have suggested a therapeutic role of JUN pathway activation in dedifferentiated liposarcoma (DDLPS) tumorigenesis. Aplidin is a drug inducing apoptosis...
BACKGROUND
Preclinical data have suggested a therapeutic role of JUN pathway activation in dedifferentiated liposarcoma (DDLPS) tumorigenesis. Aplidin is a drug inducing apoptosis through a strong, sustained activation of c-Jun NH2-terminal kinase.
METHODS
This phase II trial included patients with progressive advanced DDLPS. They received Aplidin 5 mg/m(2) days 1-15, 28-day cycle until disease progression or unacceptable toxicity. The primary end point was the 3-month nonprogression rate (PFS3) defined as the proportion of patients with nonprogressive disease at 3 months. A PFS3 of 40% considered as a reasonable objective to claim drug efficacy.
RESULTS
Between August 2012 and May 2013, 24 patients were included. Sixteen had received prior chemotherapy. Twenty-two were assessable for efficacy. The PFS3 was 9.1% [95% confidence interval (CI) 1.1-29.2]. Median progression-free and overall survivals were 1.6 months (95% CI 1.4-2.6) and 9.2 months (95% CI 6.6-). The most frequent adverse events of any grade were nausea, fatigue, anorexia, vomiting and diarrhea.
CONCLUSION
Aplidin did not meet the primary end point of this trial and do not deserve further investigation in DDLPS.
CLINICALTRIALSGOV IDENTIFIER
NCT01876043.
Topics: Aged; Aged, 80 and over; Depsipeptides; Disease Progression; Female; Follow-Up Studies; Humans; Liposarcoma; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Peptides, Cyclic; Prognosis; Survival Rate
PubMed: 26041763
DOI: 10.1093/annonc/mdv195 -
Computational Biology and Chemistry Dec 2019The low molecular weight protein tyrosine phosphatase (LMW-PTP) could regulate many signaling pathways, and it had drawn attention as a potential target for cancer. As...
The low molecular weight protein tyrosine phosphatase (LMW-PTP) could regulate many signaling pathways, and it had drawn attention as a potential target for cancer. As previous report has indicated that the aplidin could inhibit the LMW-PTP, and thus, the relevant cancer caused by the abnormal regulation of the LMW-PTP could be remission. However, the molecular mechanism of inhibition of the LMW-PTP by the aplidin had not been fully understood. In this study, various computational approaches, namely molecular docking, MDs and post-dynamic analyses were utilized to explore the effect of the aplidin on the LMW-PTP. The results suggested that the intramolecular interactions of the residues in the two sides of the active site (Ser43-Ala55 and Pro121-Asn134) and the P-loop region (Leu13-Ser19) in the LMW-PTP was disturbed owing to the aplidin, meanwhile, the π-π interaction between Tyr131 and Tyr132 might be broken. The Asn15 might be the key residue to break the residues interactions. In a word, this study may provide more information for understanding the effect of inhibition of the aplidin on the LMW-PTP.
Topics: Catalytic Domain; Depsipeptides; Enzyme Inhibitors; Humans; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Weight; Peptides, Cyclic; Protein Tyrosine Phosphatases
PubMed: 31561070
DOI: 10.1016/j.compbiolchem.2019.107123