title: Down-regulation of SerpinB2 is associated with gefitinib resistance in non-small cell lung cancer and enhances invadopodia-like structure protrusions.
abstract: The failure of targeted therapy due to the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is considered a major problem in the treatment of non-small cell lung cancer (NSCLC) patients. SerpinB2, a component of the urokinase plasminogen activator (uPA) system, has been recognized as a biomarker for the progression and metastasis of lung cancer. Nevertheless, the relationship between SerpinB2 and EGFR-TKI resistance has not been elucidated. Here, we report that SerpinB2 is down-regulated in gefitinib-resistant (H292-Gef) cells compared to gefitinib-sensitive (H292) cells. The low SerpinB2 levels in H292-Gef cells were also associated with an enhancement in invasiveness and increase in the length of invadopodia-like structures in the cells. The effect on invasiveness and gefitinib sensitivity was confirmed by knockdown and overexpression of SerpinB2. In addition, the possibility to overcome the resistance through the up-regulation of SerpinB2 was supported by employing an antitumor agent yuanhuadine (YD). Treatment with YD effectively elevated SerpinB2 levels and suppressed invasive properties in H292-Gef cells. Collectively, these findings demonstrate the prospective role of SerpinB2 as a novel biomarker for acquired gefitinib resistance and a potential target for NSCLC treatment.
authors: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Korea.
authors: Song Yi
authors: SY
authors: Bae
authors: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Korea.
authors: Hyen Joo
authors: HJ
authors: Park
authors: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Korea.
authors: Ji-Young
authors: JY
authors: Hong
authors: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Korea.
authors: Hye-Jung
authors: HJ
authors: Lee
authors: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Korea.
authors: Sang Kook
authors: SK
authors: Lee
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D017396:Plasminogen Activator Inhibitor 2 / Q000096:biosynthesis* / Q000235:genetics; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D017396:Plasminogen Activator Inhibitor 2; D011799:Quinazolines; D000077156:Gefitinib