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The molecular and clinical verification of therapeutic resistance via the p38 MAPK-Hsp27 axis in lung cancer.
- Source :
-
Oncotarget [Oncotarget] 2016 Mar 22; Vol. 7 (12), pp. 14279-90. - Publication Year :
- 2016
-
Abstract
- Unlabelled: 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.<br />Summary: DRSPs 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.
- Subjects :
- Adenocarcinoma drug therapy
Adenocarcinoma metabolism
Antineoplastic Agents pharmacology
Apoptosis drug effects
Biomarkers, Tumor
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung metabolism
Cell Proliferation drug effects
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic drug effects
HSP27 Heat-Shock Proteins genetics
Humans
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
Male
Middle Aged
Prognosis
Survival Rate
Tumor Cells, Cultured
p38 Mitogen-Activated Protein Kinases genetics
Adenocarcinoma pathology
Carcinoma, Non-Small-Cell Lung pathology
Cisplatin pharmacology
Drug Resistance, Neoplasm
HSP27 Heat-Shock Proteins metabolism
Lung Neoplasms pathology
p38 Mitogen-Activated Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26872057
- Full Text :
- https://doi.org/10.18632/oncotarget.7306