| Title: |
Revisiting the molecular interactions between the tumor protein TCTP and the drugs sertraline/thioridazine |
| Authors: |
Cherrak, Y.; Filella-Merce, I.; Schmidt, V.; Byrne, D.; Sgoluppi, V.; Chaiaheloudjou, R.; Betzi, Stéphane; Nilges, M.; Pellarin, R.; Durand, E.; Morelli, Xavier |
| Contributors: |
Laboratoire d'ingénierie des systèmes macromoléculaires (LISM); Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU); Bioinformatique structurale - Structural Bioinformatics; Institut Pasteur Paris -Centre National de la Recherche Scientifique (CNRS); ED 515 - Complexité du vivant; Sorbonne Université (SU); Institut de Microbiologie de la Méditerranée (IMM); Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS); Centre de Recherche en Cancérologie de Marseille (CRCM); Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes; Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU) |
| Source: |
ISSN: 1860-7179. |
| Publisher Information: |
HAL CCSD; Wiley-VCH Verlag |
| Publication Year: |
2021 |
| Collection: |
Archive ouverte HAL (Hyper Article en Ligne, CCSD - Centre pour la Communication Scientifique Directe) |
| Subject Terms: |
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology; [SDV.CAN]Life Sciences [q-bio]/Cancer |
| Description: |
International audience ; TCTP protein is a pharmacological target in cancer and TCTP inhibitors such as sertraline have been evaluated in clinical trials. The direct interaction of TCTP with the drugs sertraline and thioridazine has been reported in vitro by SPR experiments to be in the ~30-50 µM Kd range (Amson et al. Nature Med 2012), supporting a TCTP-dependent mode of action of the drugs on tumor cells. However, the molecular details of the interaction remain elusive although they are crucial to improve the efforts of on-going medicinal chemistry. In addition, TCTP can be phosphorylated by the Plk-1 kinase, which is indicative of poor prognosis in several cancers. The impact of phosphorylation on TCTP structure/dynamics and binding with therapeutical ligands remains unexplored. Here, we combined NMR, TSA, SPR, BLI and ITC techniques to probe the molecular interactions between TCTP with the drugs sertraline and thioridazine. We reveal that drug binding is much weaker than reported with an apparent ~mM Kd and leads to protein destabilization that obscured the analysis of the published SPR data. We further demonstrate by NMR and SAXS that TCTP S46 phosphorylation does not promote tighter interaction between TCTP and sertraline. Accordingly, we question the supported model in which sertraline and thioridazine directly interact with isolated TCTP in tumor cells and discuss alternative modes of action for the drugs in light of current literature. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/34472703; pasteur-03370569; https://hal-pasteur.archives-ouvertes.fr/pasteur-03370569; https://hal-pasteur.archives-ouvertes.fr/pasteur-03370569v3/document; https://hal-pasteur.archives-ouvertes.fr/pasteur-03370569v3/file/mBio.01348-21.pdf; PUBMED: 34472703 |
| DOI: |
10.1002/cmdc.202100528 |
| Availability: |
https://hal-pasteur.archives-ouvertes.fr/pasteur-03370569; https://hal-pasteur.archives-ouvertes.fr/pasteur-03370569v3/document; https://hal-pasteur.archives-ouvertes.fr/pasteur-03370569v3/file/mBio.01348-21.pdf; https://doi.org/10.1002/cmdc.202100528 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.B48B7B79 |
| Database: |
BASE |