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SDF‐1/CXCL12 induces directional cell migration and spontaneous metastasis via a CXCR4/Gαi/mTORC1 axis
Author(s) -
DillenburgPilla Patricia,
Patel Vyomesh,
Mikelis Constantinos M.,
ZárateBladés Carlos Rodrigo,
Doçi Colleen L.,
Amornphimoltham Panomwat,
Wang Zhiyong,
Martin Daniel,
Leelahavanichkul Kantima,
Dorsam Robert T.,
Masedunskas Andrius,
Weigert Roberto,
Molinolo Alfredo A.,
Gutkind J. Silvio
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-260083
Subject(s) - mtorc1 , cancer research , mtorc2 , pi3k/akt/mtor pathway , metastasis , cell migration , cxcr4 , biology , chemistry , microbiology and biotechnology , cell , chemokine , signal transduction , cancer , receptor , biochemistry , genetics
Multiple human malignancies rely on C‐X‐C motif chemokine receptor type 4 (CXCR4) and its ligand, SDF‐1/CXCL12 (stroma cell‐derived factor 1/C‐X‐C motif chemokine 12), to metastasize. CXCR4 inhibitors promote the mobilization of bone marrow stem cells, limiting their clinical application for metastasis prevention. We investigated the CXCR4‐initiated signaling circuitry to identify new potential therapeutic targets. We used HeLa human cancer cells expressing high levels of CXCR4 endogenously. We found that CXCL12 promotes their migration in Boyden chamber assays and single cell tracking. CXCL12 activated mTOR (mechanistic target of rapamycin) potently in a pertussis‐sensitive fashion. Inhibition of mTOR complex 1 (mTORC1) by rapamycin [drug concentration causing 50% inhibition (lC 50 ) = 5 nM] and mTORC1/mTORC2 by Torin2 (IC 50 = 6 nM), or by knocking down key mTORC1/2 components, Raptor and Rictor, respectively, decreased directional cell migration toward CXCL12. We developed a CXCR4‐mediated spontaneous metastasis model by implanting HeLa cells in the tongue of SCIDNOD mice, in which 80% of the animals develop lymph node metastasis. It is surprising that mTORC1 disruption by Raptor knockdown was sufficient to reduce tumor growth by 60% and spontaneous metastasis by 72%, which were nearly abolished by rapamycin. In contrast, disrupting mTORC2 had no effect in tumor growth or metastasis compared with control short hairpin RNAs. These data suggest that mTORC 1 may represent a suitable therapeutic target in human malignancies using CXCR4 for their meta‐static spread.—Dillenburg‐Pilla, P., Patel, V., Mikelis, C. M., Zárate‐Bladés, C. R., Doçi, C. L., Amornphimoltham, P., Wang, Z., Martin, D., Leelahavanichkul, K., Dorsam, R. T., Masedunskas, A., Weigert, R., Molinolo, A. A., Gutkind, J. S., SDF‐1/CXCL12 induces directional cell migration and spontaneous metastasis via a CXCR4/Gαi/mTORC1 axis. FASEB J. 29, 1056–1068 (2015). www.fasebj.org