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.
Highlights
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 nonsmall cell lung cancer (NSCLC) patients
We found a significant down-regulation in SERPINB2 expression in H292-Gef cells compared to the H292 cells
Several reports have suggested that low SerpinB2 expression is a biomarker of metastasis and of poor prognosis for lung cancer[4,6]
Summary
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 nonsmall cell lung cancer (NSCLC) patients. Treatment with YD effectively elevated SerpinB2 levels and suppressed invasive properties in H292-Gef cells. These findings demonstrate the prospective role of SerpinB2 as a novel biomarker for acquired gefitinib resistance and a potential target for NSCLC treatment. The role of SerpinB2 and SerpinE1 in the uPA system is to inhibit uPA through the formation of non-reversible covalent complexes with uPA These complexes interact with low-density lipoprotein receptor-related proteins (LRP) to promote endocytosis, followed by degradation[10,11]. A recent study reported that the down-regulation of SerpinB2 is associated with an acquired resistance to cisplatin in head and neck squamous cell cancer[22]
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