axis targeting CXCR4-CXCL12-CXCR7 fight mTOR inhibitor resistance in the kidney cancer -
By Afsaneh Gray, medwireNews Reporter
There is crosstalk considerably between CXCL12-CXCR4 axis CXCR7 and mammalian target of rapamycin (mTOR) pathway in carcinoma human kidney cells (RCC), and targeting the axis can overcome drug resistance to mTOR inhibitors, researchers suggest.
"Although progress mTOR inhibitors prolong -free survival in patients with advanced RCC, most patients develop resistance to agents inhibiting mTOR, which limits their effectiveness," said Stefania Scala (Istituto Nazionale per lo studio e la Cura dei Tumori, Naples, Italy) and colleagues. "[T] he new frontier of inhibition of the mTOR pathway is to identify agents that target the feedback loops and crosstalk with other pathways involved in acquired resistance to mTOR inhibitors," they add.
The chemokines and their receptors have been involved in the CCR control growth, angiogenesis and metastasis, they stress, making the chemokine receptor CXCR4-CXCL12-CXCR7 axis an attractive target for the research.
to evaluate the role of CXCR4 in mTOR signaling, the team used two RCC cell lines: A498, which expresses high levels of CXCR4; and SN12C, with low expression of CXCR4. They found that treatment with CXCL12 induced expression of two mTOR target proteins in both cell lines, and a CXCR4 antagonist inhibited this induction, suggesting that the signal CXCL12 of mTOR.
Scala and colleagues next examined the role of CXCR7 on the mTOR pathway by stimulating SN12C A498 cells with CXCL12 and CXCL11 ligand with exclusive CXCR7 in the presence of an inhibitor of CXCR7. induction of CXCL11-mediated downstream of two proteins was inhibited only by the inhibitor of CXCR7, suggesting that mTOR inhibition is also downstream of CXCR7.
The researchers also studied the role of CXCR4, CXCR7 and mTOR in cell migration and wound healing. They found that the SN12C cells and A498 have migrated to CXCL12 and CXCL11, with inhibitors of CXCR4 and CXCR7 impair this process. Treatment with mTOR inhibitor RAD001 more disturbed migration. CXCL12 and CXCL11 also induces wound healing, which has been impaired by an antagonist CXCR7 and RAD001.
Similarly, when cell growth was evaluated by the presence of inhibitors of CXCL12, CXCL11 and mTOR, the effect of inhibitors was found to be additive. Finally, the researchers note that SN12C and A498 cells that were resistant to the mTOR inhibitor RAD001 regained their drug sensitivity in the presence of CXCR4 and CXCR7 antagonists.
Writing in cell death and disease , they conclude: "All […] CXCL12-CXCR4-CXCR7 [axis] regulates mTOR signaling in kidney cancer cells, providing new opportunities and therapeutic targets to overcome resistance to mTOR inhibitors. "
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