The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer

Hae-Yun Jung; Hyun-Jung Joo; Jong Kuk Park; Yeul Hong Kim
December 2012
Cancer Research & Treatment;Dec2012, Vol. 44 Issue 4, p251
Academic Journal
Purpose c-Met is an attractive potential target for novel therapeutic inhibition of human cancer, and c-Met tyrosine kinase inhibitors (TKIs) are effective growth inhibitors of various malignancies. However, their mechanisms in anticancer effects are not clear. In the present study, we investigated the possibility that blocking c-Met signaling induces p53-mediated growth inhibition in lung cancer. Materials and Methods The growth inhibitory effects of c-Met TKI(SU11274) on lung cancer cells and axenograft model were assessed using the MTT assay, flow cytometry, and terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. The role of p53 protein in the sensitivity of c-Met TKI (SU11274) was examined by Western blot analysis and immunohis-tochemistry. Results SU11274 significantly induced apoptosis in A549 cells with wild-type p53, compared with that in Calu-1 cells with null-type p53. SU11274 increased p53 protein by enhancing the stability of p53 protein. Increased p53 protein by SU11274 induced up-regulation of Bax and PUMA expression and down-regulation of Bcl-2 expression, subsequently activating caspase 3. In p53 knock-out and knock-in systems, we confirmed that SU11274 caused apoptosis through the p53-mediated apoptotic pathway. Likewise, in the A549 xenograft model, SU11274 effectively shrank tumor volume and induced apoptosis via increased p53 protein expression. Blocking c-Met signaling increased the level of p53 protein. Conclusion Our finding suggested that p53 plays an important role in SLJ11274-induced apoptosis, and p53 status seems to be related to the sensitivity to SU11274 in lung cancer.


Related Articles

  • Icotinib.  // Reactions Weekly;Apr2014, Vol. 1497 Issue 1, p23 

    The article presents a case study of a 46-year-old man who suffered anorexia, nausea and rashes while treated with icotinib for his stage IV lung adenocarcinoma.

  • Personalized Medicine and Inhibition of EGFR Signaling in Lung Cancer. Gazdar, Adi F. // New England Journal of Medicine;9/3/2009, Vol. 361 Issue 10, p1018 

    The author discusses issues related to personalized medicine and the inhibition of epidermal growth factor receptor (EGFR) signaling in lung cancer. He says that the purpose of targeted therapies is to attack cancer-cell attributes and to prevent the possibly severe side effects of traditional...

  • Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Nelson, Valerie; Ziehr, Jacqueline; Agulnik, Mark; Johnson, Melissa // OncoTargets & Therapy;2013, Vol. 6, p135 

    The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and geitinib, are...

  • ArQule Tumbles on Survival Miss in Lung Cancer Study. Shaffer, Catherine // BioWorld Today;10/3/2012, Vol. 23 Issue 192, p1 

    The article reports on the decline in the share price of ArQule Inc. on October 1, 2012 in response to the termination of its Phase III trial of ARQ 197 in patients with nonsquamous non-small-cell lung cancer (NSCLC). ArQule Chief Executive Officer (CEO) Paolo Pucci points out the failure of the...

  • Docetaxel-carboplatin in combination with erlotinib and/or bevacizumab in patients with non-small cell lung cancer. Boutsikou, Eftimia; Kontakiotis, Theodoros; Zarogoulidis, Paul; Darwiche, Kaid; Eleptheriadou, Ellada; Porpodis, Konstantinos; Galaktidou, Grammati; Sakkas, Leonidas; Hohenforst-Schmidt, Wolfgang; Tsakiridis, Kosmas; Karaiskos, Theodoros; Zarogoulidis, Konstantinos // OncoTargets & Therapy;2013, Vol. 6, p125 

    Background: Bevacizumab and erlotinib have been demonstrated to prolong overall survival in patients with non-squamous non-small cell lung cancer (NSCLC). We designed a four-arm Phase III trial to evaluate the efficacy and toxicity of the combination of docetaxel, carboplatin, bevacizumab, and...

  • Molecular determinations of EGFR and EML4-ALK on a single slide of NSCLC tissue. Ulivi, Paola; Puccetti, Maurizio; Capelli, Laura; Chiadini, Elisa; Bravaccini, Sara; Calistri, Daniele; Zoli, Wainer; Amadori, Dino; Candoli, Piero // Journal of Clinical Pathology;Aug2013, Vol. 66 Issue 8, p708 

    Introduction Tyrosine kinase inhibitors (TKIs) and anti-anaplastic lymphoma kinase (ALK) agents are highly effective for the treatment of non-small cell lung cancer (NSCLC) patients harbouring specific alterations, and molecular characterisation of the tumour is needed even when limited tumour...

  • Patients harboring EGFR mutation after primary resistance to crizotinib and response to EGFRtyrosine kinase inhibitor. Wenxian Wang; Xiaowen Jiang, a; Zhengbo Song; Yiping Zhang // OncoTargets & Therapy;Jan2016, Vol. 9, p211 

    Anaplastic lymphoma kinase (ALK) rearrangement lung cancer responds to ALK tyrosine kinase inhibitors. It is known that many cases ultimately acquired resistance to crizotinib. However, a case of primary resistance is rare. We present a case of harboring exon 19 deletion in epidermal growth...

  • Treatment of Non-small Cell Lung Carcinoma after Failure of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. Jae Cheol Lee; Seung Hun Jang; Kye Young Lee; Young-Chul Kim // Cancer Research & Treatment;Jun2013, Vol. 45 Issue 2, p79 

    Since the first description of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation as a distinct clinical entity, studies have proved EGFR tyrosine kinase inhibitors (TKIs) as a first choice of treatment. The median response duration of TKIs as a...

  • Molecular Biomarkers for the Treatment of Lung Cancer: Personalized Therapy Beyond the EGFR Mutation. Suda, Kenichi; Mitsudomi, Tetsuya // Current Medical Literature: Lung Cancer;2013, Vol. 6 Issue 4, p91 

    The article discusses the use of molecular biomarkers to predict the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to patients with lung cancer. The authors studied whether biomarkers are predictive or prognostic in lung cancer patients. They explained...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics