The molecular and clinical verification of therapeutic resistance via the p38 MAPK–Hsp27 axis in lung cancer

// Chia-Lin Liu 1 , Su-Feng Chen 2, * , Min-Zu Wu 3 , Shu-Wen Jao 4 , Yaoh-Shiang Lin 5 , Chin-Yuh Yang 6 , Tsai-Yu Lee 4 , Lian-Wu Wen 7 , Guo-Lun Lan 7 , Shin Nieh 1, 7, * 1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 2 Department of Dental Hygiene, China Medical University, Taichung, Taiwan 3 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA 4 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 5 Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 6 Department of Dentistry, Cheng Hsin Hospital & Taipei Medical University, Taipei, Taiwan 7 Department of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Shin Nieh, e-mail: niehshin1014@yahoo.com.tw Su-Feng Chen, e-mail: su374065@gmail.com Keywords: cisplatin-based chemotherapy, drug-resistant sphere, lung cancer, heat shock protein 27, treatment strategy Received: November 17, 2015      Accepted: January 29, 2016      Published: February 10, 2016 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. 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.