SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1.
Adipocytes
Cancer
PDHA1
ROS
SHP2
Journal
Journal of cell communication and signaling
ISSN: 1873-9601
Titre abrégé: J Cell Commun Signal
Pays: Netherlands
ID NLM: 101308338
Informations de publication
Date de publication:
Sep 2023
Sep 2023
Historique:
received:
12
05
2022
accepted:
10
08
2022
medline:
9
9
2022
pubmed:
9
9
2022
entrez:
8
9
2022
Statut:
ppublish
Résumé
Adipocytes are the most abundant cell type in the adipose tissue, and their dysfunction is a significant driver of obesity-related pathologies, such as cancer. The mechanisms that (1) drive the maintenance and secretory activity of adipocytes and (2) mediate the cancer cellular response to the adipocyte-derived factors are not fully understood. To address that gap of knowledge, we investigated how alterations in Src homology region 2-containing protein (SHP2) activity affect adipocyte function and tumor crosstalk. We found that phospho-SHP2 levels are elevated in adipose tissue of obese mice, obese patients, and differentiating adipocytes. Immunofluorescence and immunoprecipitation analyses as well as in-silico protein-protein interaction modeling demonstrated that SHP2 associates with PDHA1, and that a positive association promotes a reactive oxygen species (ROS)-driven adipogenic program. Accordingly, this SHP2-PDHA1-ROS regulatory axis was crucial for adipocyte maintenance and secretion of interleukin-6 (IL-6), a key cancer-promoting cytokine. Mature adipocytes treated with an inhibitor for SHP2, PDHA1, or ROS exhibited an increased level of pro-lipolytic and thermogenic proteins, corresponding to an increased glycerol release, but a suppression of secreted IL-6. A functional analysis of adipocyte-cancer cell crosstalk demonstrated a decreased migration, invasion, and a slight suppression of cell cycling, corresponding to a reduced growth of pancreatic cancer cells exposed to conditioned media (CM) from mature adipocytes previously treated with inhibitors for SHP2/PDHA1/ROS. Importantly, PDAC cell growth stimulation in response to adipocyte CM correlated with PDHA1 induction but was suppressed by a PDHA1 inhibitor. The data point to a novel role for (1) SHP2-PDHA1-ROS in adipocyte maintenance and secretory activity and (2) PDHA1 as a regulator of the pancreatic cancer cells response to adipocyte-derived factors.
Identifiants
pubmed: 36074246
doi: 10.1007/s12079-022-00691-1
pii: 10.1007/s12079-022-00691-1
pmc: PMC10409927
doi:
Types de publication
Journal Article
Langues
eng
Pagination
575-590Subventions
Organisme : NCI NIH HHS
ID : P30 CA168524
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA231052
Pays : United States
Organisme : NCI NIH HHS
ID : CA231052
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103326
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201135
Pays : United States
Informations de copyright
© 2022. The Author(s).
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