ABSTRACT
GRP78 conducts protein folding and quality control in the ER and shows elevated expression and cell surface translocation in advanced tumors. However, the underlying mechanisms enabling GRP78 to exert novel signaling functions at cell surface are just emerging. CD44 is a transmembrane protein and an important regulator of cancer metastasis, and isoform switch of CD44 through incorporating additional variable exons to the extracellular juxtamembrane region is frequently observed during cancer progression. Using super-resolution dual-color single-particle tracking, we report that GRP78 interacts with CD44v in plasma membrane nanodomains of breast cancer cells. We further show that targeting cell surface GRP78 by the antibodies can effectively reduce cell surface expression of CD44v and cell spreading of tamoxifen-resistant breast cancer cells. Our results uncover new functions of GRP78 as an interacting partner of CD44v and as a regulator of CD44v membrane homeostasis and cell spreading. This study also provides new insights into anti-CD44 therapy in tamoxifen-resistant breast cancer.
Subject(s)
Breast Neoplasms/metabolism , Drug Resistance, Neoplasm , Heat-Shock Proteins/metabolism , Hyaluronan Receptors/metabolism , Actins/metabolism , Cell Membrane/metabolism , Endoplasmic Reticulum Chaperone BiP , Female , Gene Expression Regulation, Neoplastic , Homeostasis , Humans , Hyaluronan Receptors/chemistry , MCF-7 Cells , Neoplastic Cells, Circulating/metabolism , Signal Transduction , TamoxifenABSTRACT
Circulating tumor cells (CTCs) are a subset of cancer cells that are shed from the primary or metastatic tumors into the bloodstream. CTCs are responsible for the establishment of blood-borne distant metastases but their rarity, estimated at one CTC per billion blood cells, presents the biggest technical barrier to their functional studies. Recent advances in CTC isolation technology have allowed for the reliable capture of CTCs from the whole blood of cancer patients. The ability to derive clinically relevant information from CTCs isolated through a blood draw allows for the monitoring of active disease, avoiding the invasiveness inherent to traditional biopsy techniques. This review will summarize recent developments in CTC isolation technology; the development of CTC-derived models; the unique molecular characteristics of CTCs at the transcriptomic, genomic, and proteomic levels; and how these characteristics have been correlated to prognosis and therapeutic efficacy. Finally, we will summarize the recent findings on several signaling pathways in CTCs and metastasis. The study of CTCs is central to understanding cancer biology and promises a "liquid biopsy" that can monitor disease status and guide therapeutic management in real time.
Subject(s)
Liquid Biopsy/methods , Neoplasm Metastasis , Neoplastic Cells, Circulating , Cell Count , Cell Separation , Epithelial-Mesenchymal Transition , Humans , Receptor, ErbB-2/analysis , Transforming Growth Factor beta/physiology , Wnt Signaling PathwayABSTRACT
BACKGROUND: There is growing awareness of secondary insulin resistance and alterations in myocardial glucose utilization in congestive heart failure. Whether therapies that directly target these changes would be beneficial is unclear. We previously demonstrated that acute blockade of the insulin responsive facilitative glucose transporter GLUT4 precipitates acute decompensated heart failure in mice with advanced dilated cardiomyopathy. Our current objective was to determine whether pharmacologic enhancement of insulin sensitivity and myocardial glucose uptake preserves cardiac function and survival in the setting of primary heart failure. METHODOLOGY/PRINCIPAL FINDINGS: The GLP-1 agonist exenatide was administered twice daily to a murine model of dilated cardiomyopathy (TG9) starting at 56 days of life. TG9 mice develop congestive heart failure and secondary insulin resistance in a highly predictable manner with death by 12 weeks of age. Glucose homeostasis was assessed by measuring glucose tolerance at 8 and 10 weeks and tissue 2-deoxyglucose uptake at 75 days. Exenatide treatment improved glucose tolerance, myocardial GLUT4 expression and 2-deoxyglucose uptake, cardiac contractility, and survival over control vehicle-treated TG9 mice. Phosphorylation of AMP kinase and AKT was also increased in exenatide-treated animals. Total myocardial GLUT1 levels were not different between groups. Exenatide also abrogated the detrimental effect of the GLUT4 antagonist ritonavir on survival in TG9 mice. CONCLUSION/SIGNIFICANCE: In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial.
