title: The molecular and clinical verification of therapeutic resistance via the p38 MAPK-Hsp27 axis in lung cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department of Dental Hygiene, China Medical University, Taichung, Taiwan.
authors.forename: Su-Feng
authors.initials: SF
authors.lastname: Chen
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Min-Zu
authors.initials: MZ
authors.lastname: Wu
authors.affiliation: Institute of Environmental and Occupational Health Sciences, School of Medicine & Division of Colon and Rectum Surgery, Department of Surgery, National Yang-Ming University & National Defense Medical Center, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Jao
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Yaoh-Shiang
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Department of Dentistry, Cheng Hsin Hospital & Taipei Medical University, Taipei, Taiwan.
authors.forename: Chin-Yuh
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Institute of Environmental and Occupational Health Sciences, School of Medicine & Division of Colon and Rectum Surgery, Department of Surgery, National Yang-Ming University & National Defense Medical Center, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan.
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Department of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Lian-Wu
authors.initials: LW
authors.lastname: Wen
authors.affiliation: Department of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Guo-Lun
authors.initials: GL
authors.lastname: Lan
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Department of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Shin
authors.initials: S
authors.lastname: Nieh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D055551:HSP27 Heat-Shock Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin
keywords: cisplatin-based chemotherapy; drug-resistant sphere; heat shock protein 27; lung cancer; treatment strategy