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The Hedgehog Pathway Inhibitor GDC-0449 Alters the Expression Level of the Pathway Components In Lung Cancer Cell Lines
Lung Cancer SESSION TITLE: Lung Cancer II SESSION TYPE: Original Investigation Poster PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM
The Hedgehog Pathway Inhibitor GDC-0449 Alters the Expression Level of the Pathway Components In Lung Cancer Cell Lines Fei Tian PhD* Rosemarie Kiefl Amanda Tufman MD; and Rudolf Huber MD University Hospital of LMU, Munich, Germany PURPOSE: The hedgehog signaling pathway (Hh) has been shown to be activated in cancer. GDC-0449 (Vismodegib) is a low-molecular Hh pathway inhibitor that binds to and inhibits Hh pathway receptor SMO. Recently, we could show that GDC-0449 is effective in lung cancer cell lines and that combination with cisplatin gives an additional effect. However, no data of the effect of GDC-0449 on Hh pathway component expressions in lung cancer cell lines is available. METHODS: In order to detect the effect of GDC-0449 on the Hh pathway components, Shh, Patched, SMO, Gli-1 and Bmi-1 were examined by Western blot. RESULTS: In both HCC and H1339 cell lines, the Hh pathway components showed substantial expression. In HCC cells, after the application of GDC-0449 50 mM, Gli-1, Patched and Shh expression decreased significantly compared with the control group by 43.911.2%, 55.910.0% and 65.27.8% respectively. In H1339 cells, after the treatment, Gli-1 expression reduced significantly by 46.88.9% and Shh and Bmi-1 expression increased by 100.76.2% and 120.18.0% compared with the control group (n ¼ 3). CONCLUSIONS: The stable expression of the Hh pathway proteins provides evidence of persistent activation of Hh signaling in lung cancer. GDC-0449 inhibits the Hh pathway function effectively by affecting the protein expression of the pathway partners, but in the two different cell lines, various mechanism presents and especially in SCLC H1339 cells, a compensation regulation might take place by the autocrine Shh and the up regulation of the expression of cancer stem cell related Bmi-1. CLINICAL IMPLICATIONS: The further understanding of Hedgehog pathway’s function in lung cancer will cast a light into the application of GDC-0449 and other Hh pathway inhibitors in lung cancer therapy. DISCLOSURE: The following authors have nothing to disclose: Fei Tian, Rosemarie Kiefl, Amanda Tufman, Rudolf Huber No Product/Research Disclosure Information DOI:
http://dx.doi.org/10.1016/j.chest.2016.02.312
journal.publications.chestnet.org
LUNG CANCER
Copyright ª 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
299A
The Hedgehog Pathway Inhibitor GDC-0449 Alters the Expression Level of the Pathway Components In Lung Cancer Cell Lines Fei Tian PhD* Rosemarie Kiefl Amanda Tufman MD; and Rudolf Huber MD University Hospital of LMU, Munich, Germany PURPOSE: The hedgehog signaling pathway (Hh) has been shown to be activated in cancer. GDC-0449 (Vismodegib) is a low-molecular Hh pathway inhibitor that binds to and inhibits Hh pathway receptor SMO. Recently, we could show that GDC-0449 is effective in lung cancer cell lines and that combination with cisplatin gives an additional effect. However, no data of the effect of GDC-0449 on Hh pathway component expressions in lung cancer cell lines is available. METHODS: In order to detect the effect of GDC-0449 on the Hh pathway components, Shh, Patched, SMO, Gli-1 and Bmi-1 were examined by Western blot. RESULTS: In both HCC and H1339 cell lines, the Hh pathway components showed substantial expression. In HCC cells, after the application of GDC-0449 50 mM, Gli-1, Patched and Shh expression decreased significantly compared with the control group by 43.911.2%, 55.910.0% and 65.27.8% respectively. In H1339 cells, after the treatment, Gli-1 expression reduced significantly by 46.88.9% and Shh and Bmi-1 expression increased by 100.76.2% and 120.18.0% compared with the control group (n ¼ 3). CONCLUSIONS: The stable expression of the Hh pathway proteins provides evidence of persistent activation of Hh signaling in lung cancer. GDC-0449 inhibits the Hh pathway function effectively by affecting the protein expression of the pathway partners, but in the two different cell lines, various mechanism presents and especially in SCLC H1339 cells, a compensation regulation might take place by the autocrine Shh and the up regulation of the expression of cancer stem cell related Bmi-1. CLINICAL IMPLICATIONS: The further understanding of Hedgehog pathway’s function in lung cancer will cast a light into the application of GDC-0449 and other Hh pathway inhibitors in lung cancer therapy. DISCLOSURE: The following authors have nothing to disclose: Fei Tian, Rosemarie Kiefl, Amanda Tufman, Rudolf Huber No Product/Research Disclosure Information DOI:
http://dx.doi.org/10.1016/j.chest.2016.02.312
journal.publications.chestnet.org
LUNG CANCER
Copyright ª 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
299A