CXCR4 is a G protein-coupled receptor of considerable biological significance, and among its numerous functions, it is suggested to play a critical role in cancer metastasis. We have investigated the expression and function of CXCR4 in a range of breast cancer cell lines covering a spectrum of invasive phenotypes and found that, while surface levels of CXCR4 were uniform across the entire panel, only highly invasive cells that are metastatic in immunocompromised mice expressed functional receptors. CXCL12/SDF-1 induced cellular responses such as calcium mobilization, actin polymerization, and chemotaxis in metastatic cells, whereas noninvasive cells were unresponsive. Moreover, CXCL12 activated multiple signaling pathways downstream of G proteins in highly invasive cells but failed to activate any of the examined kinase cascades in noninvasive cell lines. This blockade in nonmetastatic cell lines seems to be due to the inability of G protein A and B subunits to form a heterotrimeric complex with CXCR4. GA and GB were able to bind to CXCR4 independently in all cell lines, but the association of G protein AB; heterotrimers with the receptor, a prerequisite for signal transduction downstream from G protein-coupled receptors, was only observed in the highly invasive cell lines. Our findings show, for the first time, that CXCR4 function is subject to complex and potentially tightly controlled regulation in breast cancer cells via differential G protein-receptor complex formation, and this regulation may play a role in the transition from nonmetastatic to malignant tumors. (Cancer Res 2006; 66(8): 4117-24)
In the multimolecular environment in tissues and organs, crosstalk between growth factor and G protein-coupled receptors is likely to play an important role in both normal and pathological responses. In this report, we demonstrate transactivation of the chemokine receptor CXCR4 by the growth factor insulin-like growth factor (IGF) The G protein-coupled receptor (GPCR) 2 CXCR4 is the receptor for the chemokine CXCL12. Both molecules are essential for life, with genetic deletion in mice of either CXCR4 or CXCL12 resulting in a lethal phenotype (1-3). Activation of CXCR4 by CXCL12 has been implicated in the homeostasis and activation of the immune system, and influences a range of other biological systems under both normal and pathological conditions (4 -6). These include angiogenesis (7-9), cell survival (10, 11), and more recently, tumor growth and metastasis (12)(13)(14). Indeed, it has recently been shown that CXCR4 is expressed in breast cancer tissues and cell lines, and that CXCL12 is expressed in several target organs of breast cancer metastasis (13). Additionally, treatment of mice with neutralizing Abs against CXCR4 inhibits metastasis in a mouse model of breast cancer, as does RNAi-mediated knockdown of CXCR4 on orthotopically transplanted breast carcinoma cells (12, 13). These data point to an important role for CXCR4 in cancer.-The cellular signal transduction pathways induced by CXCL12 have been well characterized in leukocytes. Interaction of CXCL12 with CXCR4 leads to the release of the G protein subunits G i ␣ and G␥ from intracellular domains of CXCR4. These subunits then bind and activate downstream enzyme systems including phospholipase C, which leads to a transient increase in the level of intracellular Ca 2ϩ , and phosphoinositide 3-kinase (PI3K), which results in activation of AKT and subsequently, cell migration (15-17). In contrast, the role of CXCR4, including characterization of signal transduction mechanisms in cell types other than leukocytes is less well established despite the fact that CXCR4 is expressed in most tissues and organs.Cross-talk between GPCRs and growth factor receptor-tyrosine kinase (RTKs) induced signaling pathways has become increasingly well documented in different cellular systems. For example, EGFR is tyrosine-phosphorylated in response to CCL11, a ligand for the GPCR CCR3, leading to MAP kinase activation and IL-8 production in bronchial epithelial cells (18). In rat aortic vascular smooth muscle cells, both PDGFR and EGFR are phosphorylated by sphingosine 1-phosphate (S1P), a lipid mediator that is a ligand for the S1PR family of GPCRs, leading to activation of effectors downstream of PDGFR and EGFR including Shc, and the p85 regulatory subunit of the class IA PI3K (19). In contrast, examples of transactivation of GPCRs by RTKs are less abundant, although recently it has been shown that IGF-1 stimulated phosphorylation of CCR5 in MCF-7 cells. Chemotaxis induced by IGF-1 was inhibited by a neutralizing anti-CCL5 antibody, which indicates that transactivation of ...
Resistance to anoikis, a cell-detachment induced apoptosis, is one of the malignant phenotypes which support tumor metastasis. Molecular mechanisms underlying the establishment of this phenotype require further investigation. This study aimed at exploring protein expression profiles associated with anoikis resistance of a metastatic breast cancer cell. Cell survival of suspension cultures of non-metastatic MCF-7 and metastatic MDA-MB-231 cells were compared with their adherent cultures. Trypan blue exclusion assays demonstrated a significantly higher percentage of viable cells in MDA-MB-231 than MCF-7 cell cultures, consistent with analysis of annexin V-7-AAD stained cells indicating that MDA-MB-231 possess anti-apoptotic ability 1.7 fold higher than MCF-7 cells. GeLC-MS/MS analysis of protein lysates of MDA-MB-231 and MCF-7 cells grown under both culture conditions identified 925 proteins which are differentially expressed, 54 of which were expressed only in suspended and adherent MDA-MB-231 but not in MCF-7 cells. These proteins have been implicated in various cellular processes, including DNA replication and repair, transcription, translation, protein modification, cytoskeleton, transport and cell signaling. Analysis based on the STITCH database predicted the interaction of phospholipases, PLC and PLD, and 14-3-3 beta/alpha, YWHAB, with the intrinsic and extrinsic apoptotic signaling network, suggesting putative roles in controlling anti-anoikis ability. MDA-MB-231 cells grown in the presence of inhibitors of phospholipase C, U73122, and phospholipase D, FIPI, demonstrated reduced ability to survive in suspension culture, indicating functional roles of PLC and PLD in the process of anti-anoikis. Our study identified intracellular mediators potentially associated with establishment of anoikis resistance of metastatic cells. These proteins require further clarification as prognostic and therapeutic targets for advanced breast cancer.
Background Sarcopenia, defined as a loss of muscle mass, has become a major health problem in older people. Few prospective studies report the incidence and risk of sarcopenia. Therefore, this study aimed to explore the prevalence of sarcopenia at the baseline and follow-up after 2 years in community-dwelling older Thai individuals. Methods In 2019, 330 older people were recruited from a community-dwelling population, and these participants were requested to present again in 2021. Sarcopenia was diagnosed using the criteria for the Asia Working Group for Sarcopenia (AWGS). All participants were asked to perform a 6-meter walk test, handgrip strength test, and bioelectric impedance assessment, and complete the Global Physical Activity Questionnaire. Results The study found that the prevalence of sarcopenia was 65 (19.70%) in 330 older people in 2019, and 44 of 205 participants (21.46%) were reported to have sarcopenia after 2 years. The incidence of sarcopenia was noted to be 2.44% in 2021. Analysis with ANOVA and pairwise comparisons showed that the reversibility of sarcopenia was attributed to high level of physical activity in the 2-year follow-up group (p = 0.014, 95% CI [−1753.25–−195.49]). Further, participants with moderate and high physical activity had a reduced incidence of sarcopenia (odds ratio = 9.00 and 14.47, respectively). Therefore, low physical activity in older people led to the development of sarcopenia from the baseline to the 2-year follow-up, indicating that increased physical activity may be useful in reversing sarcopenia, as suggested in the 2-year follow-up study. Low physical activity could be a risk factor for the incidence of sarcopenia. Hence, the prevention of sarcopenia could promote health improvement through moderate to high physical activity.
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