Chemoresistance of Lung Cancer Stemlike Cells Depends on Activation of Hsp27

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. Cancer 2011; 117: 1516-28. (C) 2010 American Cancer Society.