title: Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis.
abstract: Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it preferentially induces apoptosis in human cancer over normal cells. Most tumor cells, including lung cancer cell line A549, unfortunately, are resistant to TRAIL treatment even at high dose. Recent studies indicated that TRAIL-resistant cancer cells could be sensitized to TRAIL by combination therapy. Stress and heat shock proteins such as HSP90, HSP70 and HSP27 are induced in response to a wide variety of physiological environmental insults including heat, reactive oxygen species or anticancer drugs. Their elevated expressions facilitate cells to survive in stress circumstances. The HSP27 expression is enhanced in many tumor cells, implying that it is involved in tumor progression and the development of treatment resistance in various tumors, including lung cancer. This fact suggests a novel strategy for the treatment of cancer via inhibiting the function of HSP27. In this study, we investigated the inhibitory effect of a small interfering (si) RNA on the expression of HSP27 gene in the TRAIL-resistant human lung adenocarcinoma cell line A549, and the effect of HSP27 siRNA on drug sensitization of A549 cells to TRAIL treatment. The results showed that treatment of A549 cells with HSP27 siRNA down-regulated HSP27 expression but did not induce significant apoptosis. However, combination of HSP27 siRNA with TRAIL-induced significant apoptosis in TRAIL-resistant A549 cells. In addition to inducing caspases activation and apoptosis, combined treatment with HSP27 siRNA and TRAIL also increased JNK and p53 expression and activity. Collectively, these findings provide a conclusion that siRNA targeting of the HSP27 gene specifically down-regulated HSP27 expression in A549 cells, and sensitized the cells to TRAIL-induced apoptosis.
authors.affiliation: Jiangsu Center of Hepatobiliary Diseases, The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, Nanjing 210093, Jiangsu, PR China.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Zhuang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.forename: Kui
authors.initials: K
authors.lastname: Qian
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.forename: Lin
authors.initials: L
authors.lastname: Cao
authors.forename: Qilai
authors.initials: Q
authors.lastname: Huang
authors.forename: Shufeng
authors.initials: S
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Dou
authors.forename: Jen-Fu
authors.initials: JF
authors.lastname: Chiu
authors.forename: Xue-Xun
authors.initials: XX
authors.lastname: Fang
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Zi-Chun
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D048670:MAP Kinase Kinase 4; D020169:Caspases