Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer
| Autor: | X. Shirley Liu, Jiaxin Wu, Bin Gui, Adam S. Kibel, Shahrzad Rafiei, Li Jia |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cancer Research Mice SCID urologic and male genital diseases Transfection Article Metastasis Androgen deprivation therapy 03 medical and health sciences chemistry.chemical_compound Prostate cancer Mice Random Allocation 0302 clinical medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Nitriles Phenylthiohydantoin Medicine Enzalutamide Animals Humans Molecular Targeted Therapy Molecular Biology Macrophage Migration-Inhibitory Factors PI3K/AKT/mTOR pathway Receptors CXCR Mice Inbred ICR Akt/PKB signaling pathway business.industry Cancer medicine.disease Xenograft Model Antitumor Assays Androgen receptor Intramolecular Oxidoreductases Prostatic Neoplasms Castration-Resistant 030104 developmental biology Oncology chemistry Receptors Androgen 030220 oncology & carcinogenesis Benzamides PC-3 Cells Cancer research business Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Molecular cancer research : MCR. 17(1) |
| ISSN: | 1557-3125 |
| Popis: | Although androgen deprivation therapy (ADT) is an effective treatment for metastatic prostate cancer, incurable castration-resistant prostate cancer (CRPC) inevitably develops. Importantly, androgen receptor (AR) continues to be critical for prostate cancer growth and progression after ADT. One of the underlying molecular mechanisms is derepression of AR-repressed genes involved in cell cycle and proliferation after ADT. Here, the data demonstrate that C-X-C chemokine receptor type 7 (CXCR7), a seven-transmembrane G-protein–coupled chemokine receptor, is an AR-repressed gene and is upregulated after ADT. AR directly regulates CXCR7 using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Macrophage migration inhibitory factor (MIF) was identified as a ligand for CXCR7, which induces expression of cell-cycle genes through activating AKT signaling pathway. Previous studies have been focused on chemokine CXCL12 and its receptor CXCR4 in mediating metastasis of various cancer types, including prostate cancer. The critical roles of CXCL12/CXCR4 axis in the interaction between cancer cells and their microenvironment render it a promising therapeutic target in cancer treatment. The data suggest that the MIF/CXCR7/AKT pathway drives CRPC growth and metastasis independent of the CXCL12/CXCR4 axis. Furthermore, CXCR7 blockade in combination with anti-androgen enzalutamide inhibits CRPC tumor growth and potentially prevents metastasis. Notably, both MIF and CXCR7 are overexpressed in CRPC patient specimens and therefore are attractive therapeutic targets for these patients. Implications: This work suggests that CXCR7 plays more important roles than CXCR4 in CRPC progression; thus, targeting CXCR7 in combination with anti-androgen is a promising therapeutic approach for metastatic CRPC. |
| Databáze: | OpenAIRE |
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