Functional and Clinical Characterization of the Putative Tumor Suppressor WWOX in Non-small Cell Lung Cancer Silvan Becker, MD, Boyka Markova, PhD, Rainer.

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Functional and Clinical Characterization of the Putative Tumor Suppressor WWOX in Non-small Cell Lung Cancer Silvan Becker, MD, Boyka Markova, PhD, Rainer Wiewrodt, MD, Sandra Hoffarth, Patricia S. Hähnel, PhD, Sina Pleiner, MSc, Lars Hennig Schmidt, MD, Frank Breitenbuecher, PhD, Martin Schuler, MD Journal of Thoracic Oncology Volume 6, Issue 12, Pages 1976-1983 (December 2011) DOI: 10.1097/JTO.0b013e31822e59dd Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1. WWOX inhibits clonogenic survival of non-small cell lung cancer (NSCLC) cells in vitro. A549, NCI-H460, and H1299 cells, transduced with wt-WWOX or WWOXA132T mutant, were seeded in six-well plates. WWOX expression was induced by addition of doxycycline (+Dox) in the culture medium. Developing colonies were stained after 5 to 7 days incubation. Representative photomicrographs of at least three independent experiments. Journal of Thoracic Oncology 2011 6, 1976-1983DOI: (10.1097/JTO.0b013e31822e59dd) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2. Inhibition of tumor growth by WWOX in a murine xenograft model. Growth of A549-WWOX (A) and A549-WWOXA132T (B) xenografts in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice treated with doxycycline (+Dox, closed triangles) or vehicle (−Dox, open boxes). C, Immunohistochemical analysis of transgene expression in response to doxycycline treatment from explanted A549-WWOX tumors. IRS, immunoreactivity score; 12 = strongly positive. Journal of Thoracic Oncology 2011 6, 1976-1983DOI: (10.1097/JTO.0b013e31822e59dd) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3. WWOX expression is associated with an improved outcome in patients with surgically treated non-small cell lung cancer (NSCLC) cancer. A, Representative photomicrographs of immunohistochemical stainings of NSCLC with absent (IRS = 0), weak (actual immunoreactivity score [IRS] in brackets), moderate, and strong endogenous WWOX expression. B, Kaplan-Meier Plot of overall survival of a cohort of 85 patients with surgically resected NSCLC in relationship to WWOX expression status. Patients with WWOX-positive tumors (yellow line) showed a significantly improved survival (p = 0.022, Log rank [Mantel Cox] test), when compared with patients with WWOX-negative tumors (blue line). Journal of Thoracic Oncology 2011 6, 1976-1983DOI: (10.1097/JTO.0b013e31822e59dd) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4. WWOX protects lung cancer cells against apoptosis induced by staurosporine and genistein. A, A549-WWOX cells (left), NCl-H460-WWOX cells (center), and NCI-H1299-WWOX cells (right) were treated for 48 hours with indicated concentrations of staurosporine in WWOX-induced (+Dox) or -uninduced (−Dox) state. Cells were permeabilized and stained with propidium iodide, and the percentage of cells with sub-G1 DNA content, corresponding to apoptotic cells, was determined by flow cytometry. B, A549-WWOX cells (left), NCl-H460-WWOX cells (center), and NCI-H1299-WWOX cells (right) were treated for 48 hours with indicated concentrations of genistein in WWOX-induced (+Dox) or -uninduced (−Dox) state. The fraction of apoptotic cells was determined as in (A). A549-WWOX and NCl-H460-WWOX cells in WWOX-induced (+Dox) or -uninduced (−Dox) state were treated for 48 hours with etoposide (12.5 μM, C) or UV-C irradiation (20 mJ/cm2, D). Apoptosis was determined as in (A). E, Apoptosis induction in A549-WWOX cells on 48 hours treatment with 25 or 50 μM of ABT-737 in WWOX-induced (+Dox) or -uninduced (−Dox) state. Mean values ± standard deviation from three independent experiments ***p < 0.0002 ** p = 0.0086; *p < 0.0374 (unpaired t test). Journal of Thoracic Oncology 2011 6, 1976-1983DOI: (10.1097/JTO.0b013e31822e59dd) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5. Modulation of cell signaling by the kinase inhibitors staurosporine and genistein. A, A549-rtTA (control cells) and A549-WWOX cells (upper panel) and NCI-H460-WWOX cells (lower panel) cultured in the presence (+) or absence of doxycycline (−Dox) were left untreated or were incubated for 4 hours with 250 μM staurosporine or 100 μM genistein. Cellular lysates were analyzed by immunoblotting using the indicated primary antibodies. B, A549-rtTA (control cells) and A549-WWOX cells were starved over night in Dulbecco's Modified Eagle Medium containing 0.5% fetal calf serum (FCS). This was followed by stimulation with Dulbecco's Modified Eagle Medium containing 10% FCS and sequential (20 minutes) or simultaneous (4 hours) incubation with genistein (Gen, STS, 250 μM, lower panel) as indicated. Journal of Thoracic Oncology 2011 6, 1976-1983DOI: (10.1097/JTO.0b013e31822e59dd) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions