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Fig. 7 | Journal of Experimental & Clinical Cancer Research

Fig. 7

From: Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway

Fig. 7

Sulfarotene inhibits SOS2-RAS nexus and reverses sorafenib resistance. a Immunoblots of whole cell lysates or RAF-RBD precipitated lysates from HCC TRCs after treatment with 5 µM sulfarotene, 10 µM sorafenib or a combination of both drugs for 48 h. b Effects of sulfarotene on SOS2 and RAS associated pathways compared to sorafenib. HCC TRCs were treated with sulfarotene, sorafenib or their combination for 48 h as in (a). Whole cell lysates were then used to assess changes in SOS2, p-MEK1/2, p-ERK1/2 and p-AKT (Ser473) relative to their corresponding total protein levels by western blotting. c-d Effects of sulfarotene on xenograft tumor formation of the selected HCC TRCs compared to sorafenib. 1 × 105 PLC/PRF/5-TRCs were inoculated subcutaneously to the flanks in nude mice. 7 days later, 0.22 and 2.2 mg/kg sulfarotene, 30 mg/kg sorafenib or a combination of 2.2 mg/kg sulfarotene and 30 mg/kg sorafenib was injected every two days for 25 days. Sulfarotene was injected intraperitoneally while sorafenib was administered by oral intra-gastric gavage. The volume and weight (d) of the derived orthotopic xenograft tumor nodes (c) as indicated were measured. e-f Representative IHC images of the sections (e) from the orthotopic tumor nodes (c) indicate differential changes in the levels of p-ERK1/2, p-AKT, Ki-67 and Caspase-3 in response to treatment with 0.22 and 2.2 mg/kg sulfarotene, 30 mg/kg sorafenib, or a combination of 2.2 mg/kg sulfarotene and 30 mg/kg sorafenib. Bar graphs (f) show the IHC score ± SD for each group from 3 independent experiments. Tukey’s post hoc test. ***P < 0.001. ns, not significant. g Schema depicting the mechanism by which sulfarotene targets the RAR-SOS2-RAS signal axis to inhibit cancer cell growth and overcome drug resistance

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