title: Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27.
abstract: BACKGROUND
  In the current study, the authors sought to identify the molecular mechanisms underlying the chemoresistance of lung cancer stem or initiation cells (cancer stem cells).
  
  
  METHODS
  A549 lung cancer cells before and after selective enrichment of a subpopulation of cancer stem cells were treated with superoxide and traditional chemotherapeutics to determine their sensitivity or resistance to these cytotoxic agents. Apoptotic activity was measured using a variety of fluorescence-based and biochemical techniques. Specific pathways involved in the chemoresistance of cancer stem cell-enriched lung cancer cells were analyzed with Western blotting and pharmacologic targeting therapy in a xenograft model.
  
  
  RESULTS
  Lung cancer stem cells exhibited significantly decreased apoptotic response to treatment with superoxide, cisplatin, gemcitabine, or a combination of cisplatin and gemcitabine compared with control A549 cells. Apoptotic resistance was mediated through the inactivation of caspase-9 and caspase-3. Increased activation of p38MAPK, MAPKAPK2, and Hsp27 was observed in lung cancer stem cells compared with control A549 cells both before and after exposure to superoxide and chemotoxic agents. In a mouse model of lung cancer, chemotherapy-induced cells increased in the antiapoptosis pathway, and quercetin, an inhibitor of Hsp27, combined with traditional chemotherapy was effective in blocking the pathway and in the treatment of lung tumors in vivo.
  
  
  CONCLUSIONS
  The authors' data demonstrate that lung cancer stem cells have elevated levels of activated Hsp27 upon treatment with superoxide and traditional chemotherapy. When combined with chemotoxic agents, blockage of Hsp27 decreased the survival of lung cancer stem cells, which otherwise were resistant to traditional chemotherapy.
authors.affiliation: Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. hsuhs@vghtpe.gov.tw
authors.forename: Han-Shui
authors.initials: HS
authors.lastname: Hsu
authors.forename: Jiun-Han
authors.initials: JH
authors.lastname: Lin
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.forename: Tien-Wei
authors.initials: TW
authors.lastname: Hsu
authors.forename: Kelly
authors.initials: K
authors.lastname: Su
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Yo-Ting
authors.initials: YT
authors.lastname: Tsai
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011794:Quercetin / Q000494:pharmacology; D015398:Signal Transduction; D013481:Superoxides / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D013481:Superoxides; D011794:Quercetin