Academic Journal
SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1
| Τίτλος: | SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1 |
|---|---|
| Συγγραφείς: | Appolinaire A. Olou, Joe Ambrose, Jarrid L. Jack, McKinnon Walsh, Mariana T. Ruckert, Austin E. Eades, Bailey A. Bye, Prasad Dandawate, Michael N. VanSaun |
| Πηγή: | J Cell Commun Signal |
| Στοιχεία εκδότη: | Wiley, 2022. |
| Έτος έκδοσης: | 2022 |
| Θεματικοί όροι: | 2. Zero hunger, 0301 basic medicine, 0303 health sciences, 03 medical and health sciences, 3. Good health, Research Article |
| Περιγραφή: | 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. |
| Τύπος εγγράφου: | Article Other literature type |
| Γλώσσα: | English |
| ISSN: | 1873-961X 1873-9601 |
| DOI: | 10.1007/s12079-022-00691-1 |
| Σύνδεσμος πρόσβασης: | https://pubmed.ncbi.nlm.nih.gov/36074246 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . |
| Αριθμός Καταχώρησης: | edsair.doi.dedup.....5f8138574c818423a77b8f7dbbceda6a |
| Βάση Δεδομένων: | OpenAIRE |
| ISSN: | 1873961X 18739601 |
|---|---|
| DOI: | 10.1007/s12079-022-00691-1 |