Figure 7
From: KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer
Inhibition of STAT3 signaling reduces the proliferation of positive lung cancer cells. A. The inhibitors U0126, PP1 and S3I-201 reduce the colony-forming ability of KIF5B-RET positive cells. A549 cells carrying KIF5B-RET were diluted and seeded in 6-well plates, treated with DMSO, U0126 (MEK inhibitor) 10 μM, PP1 (SRC inhibitors) 5 μM or S3I-201(STAT3 inhibitors) 100 μM for 14 days. The total numbers of colonies, each containing more than 40 cells, were determined. (*P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test). B. The suppression of STAT3 reduces the cell proliferation of KIF5B-RET positive cells. A549 cells carrying KIF5B-RET were seeded in 96-well plates and treated with DMSO (0.3%) or S3I-201 (100 μM) for 72 hours, and were analyzed by MTT assay at the indicated time (***P < 0.001, Student’s t test). C. Strategies to inhibit KIF5B-RET in lung cancer therapy. KIF5B-RET fusion kinase is constitutively active without GDNF stimulation. The fusion kinase induces STAT3 Tyr705 phosphorylation directly, and also phosphorylates Tyr705 indirectly through classical JAKs /STAT3 pathway, and STAT3 transcriptional activity is further enhanced by Ser727 phosphorylation via a MEK/ERK1/2 pathway. Inhibitors at different levels of KIF5B-RET-STAT3 signaling can suppress cell proliferation triggered by KIF5B-RET in lung cancer cells.