HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia.
Adenine
/ analogs & derivatives
Case-Control Studies
Cell Line, Tumor
Cell Nucleus
/ metabolism
Cell Survival
/ drug effects
Dose-Response Relationship, Drug
Flavonoids
/ pharmacology
Flavonols
Gene Expression Regulation, Neoplastic
/ drug effects
HSP70 Heat-Shock Proteins
/ metabolism
Heat Shock Transcription Factors
/ metabolism
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
Molecular Targeted Therapy
Phosphatidylinositol 3-Kinases
/ metabolism
Piperidines
Prognosis
Proteomics
/ methods
Proto-Oncogene Proteins c-akt
/ metabolism
Pyrazoles
/ pharmacology
Pyrimidines
/ pharmacology
Signal Transduction
/ drug effects
Up-Regulation
/ drug effects
HSF1
HSP70
chronic lymphocytic leukemia
inhibition
signal transduction
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 12 2019
01 12 2019
Historique:
received:
09
11
2018
accepted:
16
04
2019
pubmed:
3
5
2019
medline:
1
2
2020
entrez:
3
5
2019
Statut:
ppublish
Résumé
Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose-dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt-Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70-low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS-regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70.
Substances chimiques
Flavonoids
0
Flavonols
0
HSF1 protein, human
0
HSP70 Heat-Shock Proteins
0
Heat Shock Transcription Factors
0
Piperidines
0
Pyrazoles
0
Pyrimidines
0
ibrutinib
1X70OSD4VX
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Adenine
JAC85A2161
fisetin
OO2ABO9578
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3089-3100Informations de copyright
© 2019 UICC.
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