STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.
AMPK
AR
CREB
LKB1
Metformin
Prostate Cancer
STAT3
mTORC1
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
12 08 2023
12 08 2023
Historique:
received:
23
03
2023
accepted:
14
07
2023
medline:
14
8
2023
pubmed:
13
8
2023
entrez:
12
8
2023
Statut:
epublish
Résumé
Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.
Identifiants
pubmed: 37573301
doi: 10.1186/s12943-023-01825-8
pii: 10.1186/s12943-023-01825-8
pmc: PMC10422794
doi:
Substances chimiques
AMP-Activated Protein Kinases
EC 2.7.11.31
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Metformin
9100L32L2N
STAT3 protein, human
0
STAT3 Transcription Factor
0
Stk11 protein, mouse
EC 2.7.11.1
Stat3 protein, mouse
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
133Subventions
Organisme : NCI NIH HHS
ID : R01 CA237027
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA240290
Pays : United States
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
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