CCL19, not CCL21 induces CCR7-mediated stimulation of leukemia apoptosis by targeting endosomal signaling signaling

Abstract

Abstract The chemokine system has emerged as a relevant target for anticancer therapy, with roles in most hallmarks of cancer. Here, the potential usefulness of CCR7 (Chemokine Receptor 7) specific agonists CCL19 (Chemokine ligand 19) and CCL21 (Chemokine ligand 21) as anti-leukemic drugs was investigated. We found that CCL19, not CCL21 was able to time-dependently decrease the proliferation and viability of Jurkat leukemic cells. This CCL19-induced cell death of leukemia is biased to CCR7 endosomal signaling but not CCR7 plasma signaling, even though the efficacy of Go/i signalling is the same. The cell death of Jurkat was accompanied by increased recycled CCR7 protein on the cell membrane; The apoptosis family members but also the MAPK system are uniquely involved, as evidenced by decreased transcription of proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B BRAF, Mitogen-Activated Protein Kinase 4 MAP4K4, Mitogen-Activated Protein Kinase 8 MAPK8 supported by RNA-Seq from Hek293_CCR7 and Jurkat leukemia. CCL19 down-regulated MAPK, suggesting CCL19 is an upstream regulator of MAPK family, which might be a mechanism of the cell death induced by CCL19. Altogether, the CCL19/CCR7 can kill leukemic cells through distinct pathways which are different from CCL21/CCR7 signalings implicating MAPK signaling events, and represent a new target of bioactive molecules with potential applications in anticancer therapy.