SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1
In: Journal of Cell Communication and Signaling, Jg. 17 (2022), Heft 3, S. 575-590
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Zugriff:
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.
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SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1
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Autor/in / Beteiligte Person: | Olou, Appolinaire A. ; Ambrose, Joe ; Jack, Jarrid L. ; Walsh, Mc ; Kinnon ; Ruckert, Mariana T. ; Eades, Austin E. ; Bye, Bailey A. ; Dandawate, Prasad ; VanSaun, Michael N. ; National Cancer Institute ; Foundation, Purnell-Wilson ; U.S. Department of Defense ; The American Gastroenterological Association Research Scholar Award |
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Zeitschrift: | Journal of Cell Communication and Signaling, Jg. 17 (2022), Heft 3, S. 575-590 |
Veröffentlichung: | Wiley, 2022 |
Medientyp: | academicJournal |
ISSN: | 1873-9601 |
DOI: | 10.1007/s12079-022-00691-1 |
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