Abstract
Treatment failure followed by relapse and metastasis in patients with non-small cell lung cancer is often the result of acquired resistance to cisplatin-based chemotherapy. A cancer stem cell (CSC)-mediated anti-apoptotic phenomenon is responsible for the development of drug resistance. The underlying molecular mechanism related to cisplatin resistance is still controversial, and a new strategy is needed to counteract cisplatin resistance. We used a nonadhesive culture system to generate drug-resistant spheres (DRSPs) derived from cisplatin-resistant H23 lung cancer cells. The expressions of drug-resistance genes, properties of CSCs, and markers of anti-apoptotic proteins were compared between control cells and DRSPs. DRSPs exhibited upregulation of cisplatin resistance-related genes. Gradual morphological alterations showing epithelial-to-mesenchymal transition phenomenon and increased invasion and migration abilities were seen during induction of DRSPs. Compared with control cells, DRSPs displayed increased CSC and anti-apoptotic properties, greater resistance to cisplatin, and overexpression of p-Hsp27 via activation of p38 MAPK signaling. Knockdown of Hsp27 or p38 decreased cisplatin resistance and increased apoptosis in DRSPs. Clinical studies confirmed that the expression of p-Hsp27 was closely associated with prognosis. Overexpression of p-Hsp27 was usually detected in advanced-stage patients with lung cancer and indicated short survival.SummaryDRSPs were useful for investigating drug resistance and may provide a practical model for studying the crucial role of p-Hsp27 in the p38 MAPK–Hsp27 axis in CSC-mediated cisplatin resistance. Targeting this axis using siRNA Hsp27 may provide a treatment strategy to improve prognosis and prolong survival in lung cancer patients.
Highlights
Lung cancer is one of the leading causes of cancerrelated deaths worldwide
Summary: drug-resistant spheres (DRSPs) were useful for investigating drug resistance and may provide a practical model for studying the crucial role of phosphorylated Hsp27 (p-Hsp27) in the p38 MAPK–Hsp27 axis in cancer stem cell (CSC)-mediated cisplatin resistance
To study the role of drug resistant (DR)-H23 cells in cisplatin-resistant lung cancer, we used western blotting to measure the expression of two important genes related to drug resistance, ABCG-2 and MDR-1 [25, 26]
Summary
Lung cancer is one of the leading causes of cancerrelated deaths worldwide. This disease is classified as either small cell lung carcinoma or non-small cell lung carcinoma (NSCLC) [1]. An aggressive type of lung cancer, NSCLC accounts for about 85% of lung cancer and is associated with poor prognosis and a low 5-year www.impactjournals.com/oncotarget survival rate [2]. Cancer recurrence followed by relapse and metastasis after therapy is the major cause of failure of lung cancer treatment and probably results from the resistance of tumors to chemotherapy [3]. Cisplatin-based chemotherapy reduces the risk of death from NSCLC by about 5% and has been reported to increase the 5-year survival after complete resection by 4.1% [6]. Despite the association of cisplatin resistance with a poor prognosis in patients with ovarian cancer, oral cancer, or lung cancer [9,10,11], the current understanding of the molecular mechanism remains contradictory
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