Abstract
Abstract Everolimus (RAD001, Afinitor) is an mTOR inhibitor FDA-approved for the treatment of patients with advanced clear cell renal cancer (RCC) after failure of treatment with sunitinib or sorafenib, or both drugs. It targets the mammalian target of rapamycin (mTOR) complex inhibiting a serine/threonine kinase regulating PI3K/AKT signaling pathway. Previous evidences demonstrated that the activation of the chemokine receptor CXCR4 involved the mTOR pathway and that CXCR4 was overexpressed in RCC. Recently, also the deorphanized chemokine receptor CXCR7 was described in RCC and defined as an independent prognostic factor. Nevertheless, little is known about the CXCR4-CXCL12-CXCR7-induced signalling. Aim of the study was to investigate if the CXCL12/CXCR4/CXCR7 complex could transduce the signal through mTOR identifying new therapeutic targets. In human renal cancer cells (RXF393, A498) treatment with CXCL12, the CXCR4 and CXCR7 ligand, induced mTOR pathway, as demonstrated through p70S6K and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) induction; the CXCL12 induction is specifically inhibited by AMD3100, a CXCR4 inhibitor, and CCX733, a CXCR7 inhibitor. The inhibition of the mTOR pathway through RAD001 treatment, inhibited CXCL12-induced pERK1/2 and chemotaxis while AMD3100 and CCX733 were not able to inhibit pERK and migration in RXF393 and A498 cell lines suggesting a role of mTOR downstream of CXCR4 and CXCR7. To analyze the CXCR7 transduction pathway the function of p38 kinase, a CXCR7 target, was evaluated. CXCL12 dramatically induced p38 MAPK in cell lines RXF393 and A498 and the p38MAPK induction was specifically inhibited by CCX733, a CXCR7 inhibitory molecule but, interestingly, p38 MAPK is dramatically induced by AMD3100, a CXCR4 antagonist. To further confirm the p38 role downstream of CXCR7, CXCL12 was unable to induce p38 phosphorylation in RXF393 cells CXCR7 siRNA transduced while inhibited by the specific CXCR7 inhibitor CCX733 in RXF393 cells. The treatment with RAD001 in human renal cancer cells inhibited the p38 induction CXCL12-mediated. This is the first evidence demonstrating that p38 is a CXCR7 target in human renal cancer cells and that AMD3100, a specific CXCR4 antagonist, potentiate the CXCL12 activity on CXCR7. Thus the combined inhibition of the three members CXCR4/CXCR7/mTOR is a valid therapeutic strategy to treat RCC inhibiting two cross talking pathways CXCR4-CXCR7 signaling to mTOR. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 891. doi:1538-7445.AM2012-891
Published Version
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