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Elucidating a key component of cancer metastasis: CXCL12 (SDF-1?) binding to CXCR4.

ABSTRACT: The chemotactic signaling induced by the binding of chemokine CXCL12 (SDF-1?) to chemokine receptor CXCR4 is of significant biological importance and is a potential therapeutic axis against HIV-1. However, as CXCR4 is overexpressed in certain cancer cells, the CXCL12:CXCR4 signaling is involved in tumor metastasis, progression, angiogenesis, and survival. Motivated by the pivotal role of the CXCL12:CXCR4 axis in cancer, we employed a comprehensive set of computational tools, predominantly based on free energy calculations and molecular dynamics simulations, to obtain insights into the molecular recognition of CXCR4 by CXCL12. We report, what is to our knowledge, the first computationally derived CXCL12:CXCR4 complex structure which is in remarkable agreement with experimental findings and sheds light into the functional role of CXCL12 and CXCR4 residues which are associated with binding and signaling. Our results reveal that the CXCL12 N-terminal domain is firmly bound within the CXCR4 transmembrane domain, and the central 24-50 residue domain of CXCL12 interacts with the upper N-terminal domain of CXCR4. The stability of the CXCL12:CXCR4 complex structure is attributed to an abundance of nonpolar and polar intermolecular interactions, including salt bridges formed between positively charged CXCL12 residues and negatively charged CXCR4 residues. The success of the computational protocol can mainly be attributed to the nearly exhaustive docking conformational search, as well as the heterogeneous dielectric implicit water-membrane-water model used to simulate and select the optimum conformations. We also recently utilized this protocol to elucidate the binding of an HIV-1 gp120 V3 loop in complex with CXCR4, and a comparison between the molecular recognition of CXCR4 by CXCL12 and the HIV-1 gp120 V3 loop shows that both CXCL12 and the HIV-1 gp120 V3 loop share the same CXCR4 binding pocket, as they mostly interact with the same CXCR4 residues.

SUBMITTER: Tamamis P

PROVIDER: S-EPMC4004218 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Elucidating a key component of cancer metastasis: CXCL12 (SDF-1α) binding to CXCR4.

Tamamis Phanourios P Floudas Christodoulos A CA

Journal of chemical information and modeling 20140408 4

The chemotactic signaling induced by the binding of chemokine CXCL12 (SDF-1α) to chemokine receptor CXCR4 is of significant biological importance and is a potential therapeutic axis against HIV-1. However, as CXCR4 is overexpressed in certain cancer cells, the CXCL12:CXCR4 signaling is involved in tumor metastasis, progression, angiogenesis, and survival. Motivated by the pivotal role of the CXCL12:CXCR4 axis in cancer, we employed a comprehensive set of computational tools, predominantly based ...[more]

PMID: 24660779

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Project description:Metastasis is the primary cause of mortality in patients with advanced gastric carcinoma, and multiple signaling pathways promote the development of this condition. Stromal cell-derived factor-1 (SDF-1α/CXCL12), the main ligand for CXC chemokine receptor-4 (CXCR4), serves an important role in gastric cancer cell migration. Previous studies have demonstrated that CXCL12 could also stimulate the secretion of epidermal growth factor receptor (EGFR) ligands, including amphiregulin and heparin-binding epidermal growth factor-like growth factor, from gastric cancer cells, resulting in an increase in the ability of migration. However, it remains to be elucidated whether CXCL12 activates EGFR intracellular signaling and therefore stimulates migration in gastric cancer. The present study demonstrated that three gastric cancer cell lines, SGC-7901, MGC-803 and BGC-823, all expressed CXCR4. The increased chemotactic migratory ability stimulated by CXCL12 was effectively abrogated by the CXCR4 antagonist, AMD3100. Furthermore, a rapid phosphorylation of Akt/extracellular signal-regulated kinase (ERK)/EGFR was demonstrated to be involved in CXCL12/CXCR4-induced gastric cancer cell migration. Knockdown of EGFR gene or the use of a monoclonal antibody against EGFR (C225) blocked the activation of ERK/Akt and partially prevented the ability of migration induced by CXCL12, which indicated that EGFR signaling is located downstream of CXCL12. In addition, it was also revealed that the activation of non-receptor tyrosine kinase c-steroid receptor co-activator (SRC) and the formation of the SRC/EGFR heterodimer are promoted by CXCL12, whereas the SRC inhibitor, PP2, blocks the SRC/EGFR heterodimer and the activation of EGFR, as well as CXCR4-meditated migration induced by CXCL12. The present results indicated that SRC mediates a potential CXCR4-EGFR cross-talk, and thereby utilizes the EGFR-Akt/ERK axis to promote cellular migration. The present study provided a novel insight into the underlying regulatory mechanisms of the CXCL12/CXCR4 pathway in gastric cancer cell migration.

Project description:The liver is the most common site of metastasis for colorectal cancer (CRC). Metastasis suppressor 1 (MTSS1), a potential tumor suppressor gene associated with tumor metastasis, has been reported to play an important role in cancer development. The present study aimed to investigate the effects and underlying mechanisms of MTSS1 on the biological behavior of CRC cells both in vitro and in vivo. A CRC mouse model with a high liver metastatic potential was established by injecting mice with SW1116 cells, and the association between MTSS1 expression levels and the metastatic potential of forming liver metastasis lesions was subsequently analyzed. MTSS1 gain‑ and loss‑of‑function experiments were performed by transfecting the CRC cell lines, SW1116 and DLD‑1, with Plvx‑IRES‑ZsGreen1‑MTSS1 plasmid and short hairpin RNA, respectively. Cell proliferation, migration, invasion and cell cycle distribution were analyzed by MTT, Transwell and flow cytometric assays, respectively. To further determine the underlying mechanisms of MTSS1 in CRC, the expression levels of cell surface chemokine C‑X‑C receptor 4 (CXCR4) and its downstream signaling factors, Rac and cell division cycle 42 (CDC42), were analyzed with or without C‑X‑C motif chemokine ligand 12 (CXCL12) stimulation. The results revealed that as the CRC metastatic potential increased, the expression levels of MTSS1 decreased. The overexpression of MTSS1 exerted an inhibitory effect on cell proliferation, migration and invasion, while the knockdown of MTSS1 exerted the opposite effects in vitro. Flow cytometric analysis and western blot analysis demonstrated that MTSS1 negatively regulated the expression levels of cell surface CXCR4 and its downstream signaling pathway activation. On the whole, the results of the present study indicate that MTSS1 may play an important negative role in CRC metastasis and the underlying mechanisms may involve the downregulation of the CXCR4/CXCL12 signaling axis.

Project description:BackgroundChronic Lymphocytic Leukemia (CLL) pathogenesis has been linked to the prolonged survival and/or apoptotic resistance of leukemic B cells in vivo, and is thought to be due to enhanced survival signaling responses to environmental factors that protect CLL cells from spontaneous and chemotherapy-induced death. Although normally associated with cell migration, the chemokine, CXCL12, is one of the factors known to support the survival of CLL cells. Thus, the signaling pathways activated by CXCL12 and its receptor, CXCR4, were investigated as components of these pathways and may represent targets that if inhibited, could render resistant CLL cells more susceptible to chemotherapy.Methodology/principal findingsTo determine the downstream signaling targets that contribute to the survival effects of CXCL12 in CLL, we took a phosphoproteomics approach to identify and compare phosphopeptides in unstimulated and CXCL12-stimulated primary CLL cells. While some of the survival pathways activated by CXCL12 in CLL are known, including Akt and ERK1/2, this approach enabled the identification of additional signaling targets and novel phosphoproteins that could have implications in CLL disease and therapy. In addition to the phosphoproteomics results, we provide evidence from western blot validation that the tumor suppressor, programmed cell death factor 4 (PDCD4), is a previously unidentified phosphorylation target of CXCL12 signaling in all CLL cells probed. Additionally, heat shock protein 27 (HSP27), which mediates anti-apoptotic signaling and has previously been linked to chemotherapeutic resistance, was detected in a subset (approximately 25%) of CLL patients cells examined.Conclusions/significanceSince PDCD4 and HSP27 have previously been associated with cancer and regulation of cell growth and apoptosis, these proteins may have novel implications in CLL cell survival and represent potential therapeutic targets. PDCD4 also represents a previously unknown signaling target of chemokine receptors; therefore, these observations increase our understanding of alternative pathways to migration that may be activated or inhibited by chemokines in the context of cancer cell survival.

Dataset Information

Elucidating a key component of cancer metastasis: CXCL12 (SDF-1?) binding to CXCR4.

Publications

Elucidating a key component of cancer metastasis: CXCL12 (SDF-1α) binding to CXCR4.

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