Cytoplasmic GPER translocation in cancer-associated fibroblasts mediates cAMP/PKA/CREB/glycolytic axis to confer tumor cells with multidrug resistance

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 F-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.

GPER‐regulated lncRNA‐Glu promotes glutamate secretion to enhance cellular invasion and metastasis in triple‐negative breast cancer

“…Our previous work has confirmed a robust cAMP-PKA signaling in GPER-activated cancer-associated fibroblasts. 33 Besides, the activation of cAMP-PKA signaling may contribute to glutamate release in cerebrocortical nerve terminals. 34 We wondered whether glutamate secretion is synergistically regulated by the GPER-cAMP-PKA signaling and GPER-lncRNA-Glu-VGLUT2 signaling in TNBC.…”

Aberrant localization of signaling proteins in skin cancer: Implications for treatment

“…Exportin 1 is a prognostic marker in lung, gastric, head and neck SCC, ovarian, breast, pancreatic, brain cancer, and osteosarcoma cancer (previously reviewed in the study by Mahipal and Malafa). In breast cancer, Yu and colleagues have shown that an aerobic glycolytic switch in cancer‐associated fibroblasts (CAFs) occurs due to increased cytoplasmic G‐protein‐coupled estrogen receptor (GPER) in an XPO1‐dependent manner . Glycolytic CAFs can then nourish surrounding breast cancer cells with mitochondrial energy in the form of lactate and pyruvate, which ultimately endows cancer cells with multidrug resistance .…”

“…In breast cancer, Yu and colleagues have shown that an aerobic glycolytic switch in cancer‐associated fibroblasts (CAFs) occurs due to increased cytoplasmic G‐protein‐coupled estrogen receptor (GPER) in an XPO1‐dependent manner . Glycolytic CAFs can then nourish surrounding breast cancer cells with mitochondrial energy in the form of lactate and pyruvate, which ultimately endows cancer cells with multidrug resistance . In myeloma cells, doxorubicin normally targets DNA‐bound topoisomerase IIα in the nucleus to induce cell death.…”

Autophagy induces transforming growth factor‐β‐dependent epithelial‐mesenchymal transition in hepatocarcinoma cells through cAMP response element binding signalling

“…This signalling pathway is regulated by adenylate cyclase and phosphodiesterase (PDE), which controls synthesis and hydrolysis of cAMP . Aberrant activation or inhibition of the cAMP/PKA/CREB pathway has been confirmed to result in cellular dysfunction and participates in tumour progression …”

“…19 Aberrant activation or inhibition of the cAMP/PKA/CREB pathway has been confirmed to result in cellular dysfunction and participates in tumour progression. 20,21 Autophagy is a lysosome-dependent protein and organelle degradation mechanism that maintains the homoeostasis of the cellular metabolic pool. This process also modulates multiple cellular signalling pathways and physiological functions by degrading redundant proteins or enzymes under stress, such as starvation or hypoxia.…”