title: Identification of ING4 (inhibitor of growth 4) as a modulator of docetaxel sensitivity in human lung adenocarcinoma.
abstract: Resistance to docetaxel (DTX) usually occurs in patients with lung adenocarcinoma. To better elucidate the underlying molecular mechanisms involved in resistance to DTX-based chemotherapy, we established a DTX-resistant lung adenocarcinoma cell line (SPC-A1/DTX). By gene array analysis, the expression of ING4 was found to be significantly downregulated in SPC-A1/DTX cells. Additionally, the decreased expression of the ING4 gene was induced upon DTX treatment of SPC-A1 cells. Overexpression of ING4 reverses DTX or paclitaxel resistance of DTX-resistant lung adenocarcinoma cells (SPC-A1/DTX or A549/Taxol) by inducing apoptosis enhancement and G₂/M arrest, and small interfering RNA-mediated ING4 knockdown renders DTX-sensitive lung adenocarcinoma cells more resistant to DTX or paclitaxel. Also, overexpression of ING4 could enhance the in vivo sensitivity of SPC-A1/DTX cells to DTX. The phenotypical changes of SPC-A1/DTX cells induced by overexpression of ING4 might be associated with the decreased ratio of Bcl-2/Bax, which resulted in the activation of caspase-3. The level of ING4 expression in tumors of nonresponding patients was significantly lower than that in those of responders, suggesting that the expression of ING4 was positively correlated with tumor response to DTX. Our results provide the first evidence that ING4 might be essential for DTX resistance in lung adenocarcinoma. Thus, ING4 will be a potential molecular target for overcoming resistance to DTX-based chemotherapies in lung adenocarcinoma.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Jiayuan
authors.initials: J
authors.lastname: Huang
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
authors.forename: Wei
authors.initials: W
authors.lastname: De
authors.forename: Longbang
authors.initials: L
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology* / Q000633:toxicity; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D043823:Taxoids; D025521:Tumor Suppressor Proteins; D000077143:Docetaxel