Abstract
Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. However, their efficacy is thought to be limited by feedback loops and crosstalk with other pathways leading to the development of drug resistance. As CXCR4–CXCL12–CXCR7 axis has been described to have a crucial role in renal cancer; the crosstalk between the mTOR pathway and the CXCR4–CXCL12–CXCR7 chemokine receptor axis has been investigated in human renal cancer cells. In SN12C and A498, the common CXCR4–CXCR7 ligand, CXCL12, and the exclusive CXCR7 ligand, CXCL11, activated mTOR through P70S6K and 4EBP1 targets. The mTOR activation was specifically inhibited by CXCR4 antagonists (AMD3100, anti-CXCR4-12G5 and Peptide R, a newly developed CXCR4 antagonist) and CXCR7 antagonists (anti-CXCR7-12G8 and CCX771, CXCR7 inhibitor). To investigate the functional role of CXCR4, CXCR7 and mTOR in human renal cancer cells, both migration and wound healing were evaluated. SN12C and A498 cells migrated toward CXCL12 and CXCL11; CXCR4 and CXCR7 inhibitors impaired migration and treatment with mTOR inhibitor, RAD001, further inhibited it. Moreover, CXCL12 and CXCL11 induced wound healing while was impaired by AMD3100, the anti CXCR7 and RAD001. In SN12C and A498 cells, CXCL12 and CXCL11 promoted actin reorganization characterized by thin spikes at the cell periphery, whereas AMD3100 and anti-CXCR7 impaired CXCL12/CXCL11-induced actin polymerization, and RAD001 treatment further reduced it. In addition, when cell growth was evaluated in the presence of CXCL12, CXCL11 and mTOR inhibitors, an additive effect was demonstrated with the CXCR4, CXCR7 antagonists and RAD001. RAD001-resistant SN12C and A498 cells recovered RAD001 sensitivity in the presence of CXCR4 and CXCR7 antagonists. In conclusion, the entire axis CXCR4–CXCL12–CXCR7 regulates mTOR signaling in renal cancer cells offering new therapeutic opportunities and targets to overcome resistance to mTOR inhibitors.
Highlights
IntroductionComprising mammalian target of rapamycin (mTOR), mLST8, rictor (rapamycin-insensitive companion of mTOR), mSin[1] (mammalian stress-activated protein kinase (SAPK)-interacting protein 1), protor (protein observed with rictor) and PRR5 (proline-rich protein 5).[4] mTOR complex 1 (mTORC1) responds to amino acids, stress, oxygen, energy and growth factors and is sensitive to rapamycin; when active, mTORC1 promotes cell growth and drives cell-cycle progression
Comprising mammalian target of rapamycin (mTOR), mLST8, rictor, mSin[1] (mammalian stress-activated protein kinase (SAPK)-interacting protein 1), protor and PRR5.[4] mTOR complex 1 (mTORC1) responds to amino acids, stress, oxygen, energy and growth factors and is sensitive to rapamycin; when active, mTORC1 promotes cell growth and drives cell-cycle progression
Temsirolimus was the first mTOR inhibitor approved as first-line treatment in patients with poor-prognosis metastatic Renal cell carcinoma (RCC) patients,[3] ridaforolimus is currently tested in phase III clinical trials[5] and RAD001 is indicated as second-line treatment in patients with RCC at failure of first-line treatment with sunitinib or sorafenib
Summary
Comprising mTOR, mLST8, rictor (rapamycin-insensitive companion of mTOR), mSin[1] (mammalian stress-activated protein kinase (SAPK)-interacting protein 1), protor (protein observed with rictor) and PRR5 (proline-rich protein 5).[4] mTORC1 responds to amino acids, stress, oxygen, energy and growth factors and is sensitive to rapamycin; when active, mTORC1 promotes cell growth and drives cell-cycle progression. CXCR7–CXCR4 heterodimers.[13] In contrast, others demonstrated that CXCR7 relays intracellular signals[14,15,16,17] and promotes cell motility[18,13,19] acting through b-arrestin.[20,21] CXCR7 is highly expressed in human cancers such as prostate, lung, glioma, ovarian, breast cancer cells and in tumor-associated blood vessels and seems to be essential for survival, adhesion and growth of tumor cells.[11,14,15,22,23,24] It was recently demonstrated that CXCR4 and CXCR7 predict prognosis in RCC.[10,25] CXCL12 activates CXCR4 and the derived signaling can transduce on the mTOR pathway in pancreatic cancer, gastric cancer and T-cell leukemia cells;[26,27,28,29] antagonists targeting PI3K and/or mTOR inhibited CXCL12mediated cell migration and this effect was primarily attributed to the inhibition of mTORC1 and consequent decrease in RhoA, Cdc[42] and Rac[1] in human gastric carcinoma cells.[28]
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