Signal Transducer and Activator of Transcription 3 as Molecular Therapy for Non–Small- Cell Lung Cancer Cheng-Yi Wang, MD, Ting-Ting Chao, PhD, Wei-Tien.

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Signal Transducer and Activator of Transcription 3 as Molecular Therapy for Non–Small- Cell Lung Cancer Cheng-Yi Wang, MD, Ting-Ting Chao, PhD, Wei-Tien Tai, PhD, Fang-Yu Chang, MS, Wen-Pin Su, MD, PhD, Yen-Lin Chen, MD, Pao- Tzu Chen, BsC, Ching-Yu Weng, BsC, Ang Yuan, MD, PhD, Chung-Wai Shiau, PhD, Chong-Jen Yu, MD, PhD, Kuen-Feng Chen, MD, PhD Journal of Thoracic Oncology Volume 9, Issue 4, Pages 488-496 (April 2014) DOI: 10.1097/JTO.0000000000000107 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 SC-1 had anticancer effects similar to sorafenib in NSCLC cells. A, Left panel, chemical structure of sorafenib or SC-1. Right panel, effect of sorafenib or SC-1 on Raf-1 activity. H460 cells were exposed to sorafenib or SC-1 at 10 μM for 24 hours. Points, mean; bars, SD (n=3). B, Dose-escalation effects of sorafenib or SC-1 on cell viability in five NSCLC cell lines. Cells were exposed to sorafenib or SC-1 at the indicated doses for 24 hours. Cell viability was measured by water-soluble tetrazolium monosodium salt–1 assay. Points, mean; bars, SD (n=3). *p < 0.05; **p < 0.01. C, Dose-escalation effects of sorafenib or SC-1 on apoptosis in five NSCLC cell lines, as analyzed by flow cytometry. Points, man; bars, SD (n=3). D, Apoptosis effects of sorafenib or SC-1 SC-1 in five NSCLS cell lines, as analyzed by Western blot. NSCLC, non–small-cell lung cancer; DMSO, dimethyl sulfoxide; PARP, poly(ADP-ribose) polymerase. Journal of Thoracic Oncology 2014 9, 488-496DOI: (10.1097/JTO.0000000000000107) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 SC-1 reduced STAT3 phosphorylation in NSCLC cells. A, Effects of sorafenib or SC-1 on STAT3-related proteins. Cells were exposed to sorafenib or SC-1 at the indicated doses for 24 hours. B, Dose-escalation (top) and time-dependent (lower) effects of sorafenib or SC-1 on phospho-STAT3 in H460 cells. Cells were treated with sorafenib or SC-1 at 10 μM for 24 hours. C, Effects of sorafenib and SC-1 on STAT3 activity, phospho-STAT3 enzyme-linked immunosorbent assay (ELISA). Points, man; bars, SD (n=3) **p < 0.01. D, Protective effects of STAT3 on apoptosis induced by sorafenib or SC-1 in H460 cells. Cells were exposed to sorfenib or SC-1 at 10 μM for 24 hours. Apoptotic cells were analyzed by flow cytometry. Columns, mean; bars, SD (n=3) **p < 0.01. E, Untreated and two drugs-treated cells were analyzed by fluorescence microscopy. DAPI staining and overlay demonstrated nuclear accumulation of STAT3 in untreated, but not in sorafenib- or SC-1–treated cells. STAT3, signal transducer and activator of transcription 3; DAPI, 4′,6-diamidino-2-phenylindole. Journal of Thoracic Oncology 2014 9, 488-496DOI: (10.1097/JTO.0000000000000107) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Inhibition of SHP-1reversed the effects of sorafenib and SC-1 on phospho-STAT3 and apoptosis. A, Left panel, vanadate, a nonspecific phosphatase inhibitor; middle panel, specific SHP-1inhibitor; right panel, specific SHP-2 inhibitor; Columns, mean; bars, SD (n=3) *p < 0.05. B, Silencing of SHP-1by siRNA reduced the effects of sorafenib or SC-1 on p-STAT3 in H460 cells. Columns, mean; bars, SD (n=3) *p < 0.05, **p < 0.01. C, Effects of sorafenib or SC-1 on protein interactions between SHP-1 and STAT3. D, Knockdown of SHP-2 and PTP-1B did not affect the effects of sorafenib or SC-1 on p-STAT3 and apoptosis. H460 cells were transfected with control siRNA or SHP-2 siRNA or PTP-1B siRNA for 48 hours then treated with sorafenib or SC-1 at 10 μM for 24 hours. SHP-1, Src homology-2 containing protein tyrosine; STAT3, signal transducer and activator of transcription 3; PTP-1B, protein-tyrosine phosphatase 1B; DMSO, dimethyl sulfoxide; IP, immunoprecipitation. Journal of Thoracic Oncology 2014 9, 488-496DOI: (10.1097/JTO.0000000000000107) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 In vivo effects of sorafenib and SC-1 on H460 and A549 xenograft nude mice. A and D, Sorafenib and SC-1 show antitumor effects on H460 and A549 tumors. Points, mean (n=8); bars, standard error. B and E, Western blot analysis of p-STAT3 and STAT3 in H460 and A549 tumors. C and F, the activities of SHP-1 in H460 and A549 tumors. Points, mean (n=8); bars, standard error. *p < 0.05; **p< 0.01. STAT3, signal transducer and activator of transcription 3; SHP-1, Src homology-2 containing protein tyrosine. Journal of Thoracic Oncology 2014 9, 488-496DOI: (10.1097/JTO.0000000000000107) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Immunohistochemical staining. Representative immunohistochemical staining patterns of p-STAT3 and STAT3 in EGFR wild-type non–small-cell lung cancer clinical specimen (magnification: 200 ×). Top panel, hematoxylin and eosin stain; middle panel, p-STAT3 stain; lower panel, STAT3 stain; right panel, Ca: cancer part of clinical specimen; left panel, N: the adjacent normal part of clinical specimen. STAT3, signal transducer and activator of transcription 3; EGFR, epidermal growth factor receptor; H&E, hematoxylin and eosin. Journal of Thoracic Oncology 2014 9, 488-496DOI: (10.1097/JTO.0000000000000107) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions