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Fig. 5 | Journal of Experimental & Clinical Cancer Research

Fig. 5

From: Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma

Fig. 5

Inhibition of oncogenic pathways regulated aberrant expression of YB-1 and ABCB-1. a Different small-molecule inhibitors for Akt/PI3K, RSK and mTOR pathways show differential activation of Akt (phosphorylation at serine-473) and ABCB1 expression levels in Caki-1WT and Caki-1 DC. b Western blot results showing significant downregulation of YB-1 and ABCB-1 protein expression when treated with 0.5 μM INK128. c RT-PCR data shows a marked change in YB-1 mRNA level with 0.5 μM INK128 in Caki-1 DC compared to Caki-1WT, but no significant difference in ABCB-1 mRNA levels. d Cell viability assay demonstrating sensitization of Caki-1 DC cells to sunitinib. The response of Caki-1WT and Caki-1 DC are comparable, and a pronounced increase in cell death is observed with the combination therapy. e To simulate sequential treatment as applied in the clinic, Caki-1WT and Caki-1 DC were treated with different doses (0.25 μM, 0.5 μM and 1 μM) of INK128 for 48 h, washed off the drug with 1X PBS and then re-challenged with 5 μM SUT for 24 h to observe re-sensitization of Caki-1 DC to sunitinib. Our data shows significant cell death with sequential treatment and the drug-resistant phenotype Caki-1 DC had substantial effect, which is comparable to the parental Caki-1WT. SUT: sunitinib, AZD5363: Akt inhibitor, AZD8186: PI3K inhibitor, LY294002: Akt/PI3K pan inhibitor, SL0101: RSK inhibitor and INK128: mTOR inhibitor. Data are mean ± SEM and normalised to matched controls, n = 3–4 independent experiments. *p < 0.05, **p < 0.01, ***p < 0.0005, ****p < 0.0001

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