Olou Appolinaire A, Ambrose Joe, Jack Jarrid L, Walsh McKinnon, Ruckert Mariana T, Eades Austin E, Bye Bailey A, Dandawate Prasad, VanSaun Michael N
Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
J Cell Commun Signal. 2023 Sep;17(3):575-590. doi: 10.1007/s12079-022-00691-1. Epub 2022 Sep 8.
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.
脂肪细胞是脂肪组织中最丰富的细胞类型，其功能障碍是肥胖相关病理（如癌症）的重要驱动因素。目前，（1）驱动脂肪细胞维持和分泌活性以及（2）介导癌细胞对脂肪细胞衍生因子反应的机制尚未完全明确。为填补这一知识空白，我们研究了含Src同源区2蛋白（SHP2）活性的改变如何影响脂肪细胞功能和肿瘤相互作用。我们发现，肥胖小鼠、肥胖患者的脂肪组织以及分化中的脂肪细胞中磷酸化SHP2水平升高。免疫荧光和免疫沉淀分析以及计算机模拟的蛋白质-蛋白质相互作用模型表明，SHP2与PDHA1相互作用，且这种正相关促进了活性氧（ROS）驱动的脂肪生成程序。因此，这个SHP2-PDHA1-ROS调节轴对于脂肪细胞的维持以及白细胞介素-6（IL-6，一种关键的促癌细胞因子）的分泌至关重要。用SHP2、PDHA1或ROS抑制剂处理成熟脂肪细胞后，脂解和产热相关蛋白水平升高，甘油释放增加，但分泌的IL-6受到抑制。对脂肪细胞与癌细胞相互作用的功能分析表明，迁移、侵袭减少，细胞周期略有抑制，这与暴露于先前用SHP2/PDHA1/ROS抑制剂处理过的成熟脂肪细胞条件培养基（CM）中的胰腺癌细胞生长减少相对应。重要的是，胰腺导管腺癌（PDAC）细胞对脂肪细胞CM的生长刺激与PDHA1诱导相关，但被PDHA1抑制剂抑制。这些数据表明：（1）SHP2-PDHA1-ROS在脂肪细胞维持和分泌活性中具有新作用；（2）PDHA1作为胰腺癌细胞对脂肪细胞衍生因子反应的调节因子。
