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CXCR1

Official Full Name
C-X-C motif chemokine receptor 1
Organism
Homo sapiens
GeneID
3577
Background
The protein encoded by this gene is a member of the G-protein-coupled receptor family. This protein is a receptor for interleukin 8 (IL8). It binds to IL8 with high affinity, and transduces the signal through a G-protein activated second messenger system. Knockout studies in mice suggested that this protein inhibits embryonic oligodendrocyte precursor migration in developing spinal cord. This gene, IL8RB, a gene encoding another high affinity IL8 receptor, as well as IL8RBP, a pseudogene of IL8RB, form a gene cluster in a region mapped to chromosome 2q33-q36. [provided by RefSeq, Jul 2008]
Synonyms
C-C; CD128; CD181; CKR-1; IL8R1; IL8RA; CMKAR1; IL8RBA; CDw128a; C-C-CKR-1;
Bio Chemical Class
GPCR rhodopsin
Protein Sequence
MSNITDPQMWDFDDLNFTGMPPADEDYSPCMLETETLNKYVVIIAYALVFLLSLLGNSLVMLVILYSRVGRSVTDVYLLNLALADLLFALTLPIWAASKVNGWIFGTFLCKVVSLLKEVNFYSGILLLACISVDRYLAIVHATRTLTQKRHLVKFVCLGCWGLSMNLSLPFFLFRQAYHPNNSSPVCYEVLGNDTAKWRMVLRILPHTFGFIVPLFVMLFCYGFTLRTLFKAHMGQKHRAMRVIFAVVLIFLLCWLPYNLVLLADTLMRTQVIQESCERRNNIGRALDATEILGFLHSCLNPIIYAFIGQNFRHGFLKILAMHGLVSKEFLARHRVTSYTSSSVNVSSNL
Open
Disease
Chronic obstructive pulmonary disease, Gout, Indeterminate colitis, Liver vascular disorder, Medical/surgical procedure injury, Melanoma, Myelodysplastic syndrome, Pain, Solid tumour/cancer, Transplant rejection, Ulcerative colitis
Approved Drug
1 +
Clinical Trial Drug
3 +
Discontinued Drug
2 +

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Detailed Information

The CXCR1 gene is part of the C-X-C chemokine receptor family and has important biological functions. This gene makes a protein that is one of the strong receptors for Interleukin 8 (IL-8) and belongs to the G protein-coupled receptor (GPCR) family. CXCR1 is a type of receptor that helps control the immune system, especially during inflammation. Recent studies show that CXCR1 is important in the tumor setting and may be a key immune receptor and a possible target for cancer treatment.

Binding Mechanism of CXCR1 Receptor and IL-8

CXCR1 needs to connect with IL-8 to work properly in the body. IL-8 works as a key chemokine, bringing leukocytes, especially neutrophils, to disease sites by binding to the CXCR1 receptor. This process, important in inflammation, triggers the downstream G protein signaling pathways, causing the phosphoinositol-calcium system to release intracellular calcium, helping immune cell recruitment and modulating immune response strength and length.CXCR1 binds IL-8 with high affinity, enabling effective signaling even at low IL-8 concentrations. Although CXCR1 and its homolog CXCR2 share signaling similarities, both activate various intracellular pathways like NF-kB, MAPK, and JAK-STAT, involved in inflammation and tumor development.

Functional Differences and Similarities Between CXCR1 and CXCR2

CXCR1 and CXCR2, both GPCRs, share approximately 76% sequence homology, binding IL-8 and similar chemokines like CXCL6. Despite overlapping ligand interactions, their cellular signaling and biological effects differ.

CXCR1 primarily induces reactive oxygen species (ROS) and oxidative bursts in neutrophils, whereas CXCR2 favors endocytic processes, especially under low IL-8 concentrations. Notably, CXCR1's role in tumors may differ, possibly serving as a cancer stem cell (CSC) marker in specific tumor types.

Figure 1 depicts pathways from CXCR1/2 activation that boost angiogenesis, cell growth, and invasiveness.Figure 1. Pathways from CXCR1/2 activation boost angiogenesis, cell growth, and invasiveness. (Molczyk C, et al., 2023)

Role of CXCR1 Axis in Inflammation

Inflammation, a critical defense mechanism, recruits immune cells against infection or injury. However, chronic inflammation may lead to tumorigenesis. The CXCR1 axis, involving its ligand IL-8, is pivotal in this process, influencing normal immune responses and promoting tumor progression within the microenvironment.

In tumors, CXCR1-IL-8 interaction enhances cell proliferation, migration, and angiogenesis, linking to cancer resistance. By modulating CXCR1 activity, cancer cells evade immune surveillance, supporting survival in harsh conditions. Thus, CXCR1 acts as a facilitator between cancer cells and the immune system.

Relationship Between CXCR1 and Cancer Stem Cells (CSCs)

CSCs are a unique tumor cell group with self-renewal and differentiation abilities, often resisting therapies, contributing to recurrence and metastasis. Recent studies suggest CXCR1's role in immune evasion, significantly impacting CSC formation and maintenance.

In various solid tumors, high CXCR1 expression correlates with cancer cell proliferation, migration, and therapy resistance. By regulating CXCR1, tumor cells enhance self-renewal, fostering CSC development, making CXCR1 a potential CSC marker and therapeutic target.

CXCR1 plays a complex role in tumors by connecting with immune cells, like macrophages and T cells, and other cells in the tissue, like fibroblasts and vascular cells. These interactions help the tumor avoid the immune system and fight treatment together.

The potential of CXCR1 as an Anti-tumor Therapeutic Target

CXCR1 plays an important part in tumors, especially in how cells move, grow, and form new blood vessels. Therefore, it is a key target for treatment. Blocking CXCR1 might lower the chances of the immune system being evaded and improve the effectiveness of chemotherapy. Right now, some drugs that block CXCR1 and CXCR2 are being tested in clinical studies for inflammatory illnesses such as COPD and asthma. In cancer studies, researchers are testing a combination of CXCR1 blockers and immune checkpoint inhibitors. The goal is to reduce CXCR1 activity and enhance the immune system to improve treatment outcomes.

References:

  1. Molczyk C, Singh RK, et al. CXCR1: A Cancer Stem Cell Marker and Therapeutic Target in Solid Tumors. Biomedicines. 2023 Feb 16;11(2):576.
  2. Che J, Song R, et al. Targeting CXCR1/2: The medicinal potential as cancer immunotherapy agents, antagonists research highlights and challenges ahead. Eur J Med Chem. 2020 Jan 1;185:111853.
  3. Ruffini PA. The CXCL8-CXCR1/2 Axis as a Therapeutic Target in Breast Cancer Stem-Like Cells. Front Oncol. 2019 Feb 6;9:40.
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