Selecting the first chemical molecule inhibitor of HSP110 for colorectal cancer therapy
Gustavo J. Gozzi
(1, 2, 3, 4)
,
Daniel Gonzalez
(1, 2, 3, 4)
,
Christophe Boudesco
(1, 2, 3, 4)
,
Alexandre M. M. Dias
(1, 2, 3, 4)
,
Guillaume Gotthard
(5)
,
Burhan Uyanik
(1, 2, 3, 4)
,
Lucile Dondaine
(1, 2, 3, 4)
,
Guillaume Marcion
(1, 2, 3, 4)
,
François Hermetet
(1, 2, 3)
,
Camille Denis
(6)
,
Laurianne Hardy
(6)
,
Peggy Suzanne
(6)
,
Romain Douhard
(1, 2, 3, 4)
,
Gaetan Jego
(1, 2, 3, 4)
,
Laurence Dubrez
(1, 2, 3, 4)
,
Oleg N. Demidov
(1, 2, 3, 4)
,
Fabrice Neiers
(4, 7)
,
Loïc Briand
(4, 7)
,
Jana Sopková-de Oliveira Santos
(6)
,
Anne-Sophie Voisin-Chiret
(6)
,
Carmen Garrido
(1, 2, 3, 4, 8)
1
LNC -
Lipides - Nutrition - Cancer [Dijon - U1231]
2 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
3 LNCC - Ligue Nationale Contre le Cancer
4 UBFC - Université Bourgogne Franche-Comté [COMUE]
5 ESRF - European Synchrotron Radiation Facility
6 CNRS - Centre National de la Recherche Scientifique
7 CSGA - Centre des Sciences du Goût et de l'Alimentation [Dijon]
8 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
2 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
3 LNCC - Ligue Nationale Contre le Cancer
4 UBFC - Université Bourgogne Franche-Comté [COMUE]
5 ESRF - European Synchrotron Radiation Facility
6 CNRS - Centre National de la Recherche Scientifique
7 CSGA - Centre des Sciences du Goût et de l'Alimentation [Dijon]
8 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
Peggy Suzanne
- Fonction : Auteur
- PersonId : 1355456
- IdHAL : peggy-suzanne
- ORCID : 0000-0002-6080-8306
Laurence Dubrez
- Fonction : Auteur
- PersonId : 183779
- IdHAL : laurence-dubrez-daloz
- ORCID : 0000-0002-7030-2181
- IdRef : 133798194
Fabrice Neiers
- Fonction : Auteur
- PersonId : 740725
- IdHAL : fabrice-neiers
- ORCID : 0000-0002-8965-4929
- IdRef : 120126923
Loïc Briand
- Fonction : Auteur
- PersonId : 736264
- IdHAL : loic-briand
- ORCID : 0000-0002-8175-5936
- IdRef : 151710279
Jana Sopková-de Oliveira Santos
- Fonction : Auteur
- PersonId : 758765
- ORCID : 0000-0002-4829-8120
Anne-Sophie Voisin-Chiret
- Fonction : Auteur
- PersonId : 767482
- ORCID : 0000-0001-5564-2244
- IdRef : 083367578
Carmen Garrido
- Fonction : Auteur
- PersonId : 992766
- ORCID : 0000-0003-1368-1493
- IdRef : 095167196
Résumé
Pro-survival stress-inducible chaperone HSP110 is the only HSP for which a mutation has been found in a cancer. Multicenter clinical studies demonstrated a direct association between HSP110 inactivating mutation presence and excellent prognosis in colorectal cancer patients. Here, we have combined crystallographic studies on human HSP110 and in silico modeling to identify HSP110 inhibitors that could be used in colorectal cancer therapy. Two molecules (foldamers 33 and 52), binding to the same cleft of HSP110 nucleotide-binding domain, were selected from a chemical library (by co-immunoprecipitation, AlphaScreening, Interference-Biolayer, Duo-link). These molecules block HSP110 chaperone anti-aggregation activity and HSP110 association to its client protein STAT3, thereby inhibiting STAT3 phosphorylation and colorectal cancer cell growth. These effects were strongly decreased in HSP110 knockdown cells. Foldamer's 33 ability to inhibit tumor growth was confirmed in two colorectal cancer animal models. Although tumor cell death (apoptosis) was noted after treatment of the animals with foldamer 33, no apparent toxicity was observed, notably in epithelial cells from intestinal crypts. Taken together, we identified the first HSP110 inhibitor, a possible drug-candidate for colorectal cancer patients whose unfavorable outcome is associated to HSP110.