A Locked, Dimeric CXCL12 Variant Effectively Inhibits Pulmonary Metastasis of CXCR4-Expressing Melanoma Cells Due to Enhanced Serum Stability

摘要: The CXC chemokine receptor-4 (CXCR4) plays a critical role in cancer by positively regulating cell metastasis and survival. We previously showed that high concentrations of the CXCR4 ligand, wild-type CXCL12 (wtCXCL12), could inhibit colorectal vivo, we have hypothesized wtCXCL12 dimerizes at concentration to become potent antagonist CXCR4. To address this hypothesis, engineered covalently-locked, dimeric variant (CXCL122). Herein, show CXCL122 can not only implantation lung CXCR4-B16-F10 melanoma cells more effectively than AMD3100, but also blocks growth established pulmonary tumors. identify basis for vivo efficacy CXCL122, performed western blot ELISA analyses, which revealed was stable least 12 hours serum whereas quickly degraded. maintained its properties vitro chemotaxis assays up 24 serum, ineffective after 6 hours. Heat-inactivation prolonged stability function hours, suggesting enzymatic degradation as possible mechanism inactivation. In analysis amino-terminal cleavage enzymes dipeptidylpeptidase IV (DPPIV/CD26) matrix metalloproteinase-2 (MMP-2) resulted 25-fold 2-fold slower rates, respectively, compared wtCXCL12. summary, our results suggest possesses greater potential an anti-metastatic drug AMD3100 or wtCXCL12, potentially due enhanced presence N-terminal degrading enzymes.