ABSTRACT
Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs. The glycolytic CAFs feed the extra pyruvate and lactate to tumor cells for augmentation of mitochondrial activity, and this energy metabolically coupled in a 'host-parasite relationship' between catabolic CAFs and anabolic cancer cells confers the tumor cells with multiple drug resistance to several conventional clinical treatments including endocrine therapy (tamoxifen), Her-2-targeted therapy (herceptin) and chemotherapy (epirubicin). Moreover, the clinical data from 18F-fluorodeoxyglucose positron emission tomography/computed tomography further present a strong association between the GPER/cAMP/PKA/CREB pathway of stromal fibroblasts with tumor metabolic activity and clinical treatment, suggesting that targeting cytoplasmic GPER in CAFs may rescue the drug sensitivity in patients with breast cancer. Thus, our data define novel insights into the stromal GPER-mediated multiple drug resistance from the point of reprogramming of tumor energy metabolism and provide the rationale for CAFs as a promising target for clinical therapy.
Subject(s)
Breast Neoplasms/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Cyclic AMP/metabolism , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/metabolism , Active Transport, Cell Nucleus , Breast Neoplasms/pathology , Cell Line, Tumor , Cytoplasm/metabolism , Drug Resistance, Neoplasm , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Glycolysis , Humans , Karyopherins/metabolism , MCF-7 Cells , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Stromal Cells/metabolism , Stromal Cells/pathology , Exportin 1 ProteinABSTRACT
A new acylated C-glycosylflavone (1) was isolated from Trollius ledebouri Reichb together with two known C-glycosyflavones (2, 3). The structures were elucidated by spectroscopic methods, including HRMS, IR, 1H and 13C NMR and 2D experiments (COSY, HMQC and HMBC). The anti-inflammatory activities of 1-3 were tested on TPA-induced mice ear edema (in vivo).