title: The mechanisms and significance of up-regulation of RhoB expression by hypoxia and glucocorticoid in rat lung and A549 cells.
abstract: Small guanosine triphosphate (GTP)-binding protein RhoB is an important stress sensor and contributes to the regulation of cytoskeletal organization, cell proliferation and survival. However, whether RhoB is involved in the hypoxic response and action of glucocorticoid (GC) is largely unknown. In this study, we investigated the effects of hypoxia or/and GC on the expression and activition of RhoB in the lung of rats and human A549 lung carcinoma cells, and further studied its mechanism and significance. We found that hypoxia and dexamethasone (Dex), a synethic GC, not only significantly increased the expression and activation of RhoB independently but also coregulated the expresion of RhoB in vitro and in vivo. Up-regulation of RhoB by hypoxia was in part through stabilizing the RhoB mRNA and protein. Inhibiting hypoxia-activated hypoxia-inducible transcription factor-1α (HIF-1α), c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) with their specific inhibitors significantly decreased hypoxia-induced RhoB expression, indicating that HIF-1α, JNK and ERK are involved in the up-regulation of RhoB in hypoxia. Furthermore, we found that knockdown of RhoB expression by RhoB siRNA not only significantly reduced hypoxia-enhanced cell migration and cell survival in hypoxia but also increased the sensitivity of cell to paclitaxel (PTX), a chemotherapeutic agent, and reduced Dex-enhanced resistance to PTX-chemotherapy in A549 cells. Taken together, the novel data revealed that hypoxia and Dex increased the expression and activation of RhoB, which is important for hypoxic adaptation and hypoxia-accelerated progression of lung cancer cells. RhoB also enhanced the resistance of cell to PTX-chemotherapy and mediated the pro-survival effect of Dex.
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, Shanghai, China.
authors.forename: Gao-Xiang
authors.initials: GX
authors.lastname: Huang
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, Shanghai, China.|Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Pan
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, Shanghai, China.
authors.forename: Yi-Duo
authors.initials: YD
authors.lastname: Jin
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
authors.forename: Xiao-Lian
authors.initials: XL
authors.lastname: Song
authors.affiliation: Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, Shanghai, China.
authors.forename: Yi-Dong
authors.initials: YD
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D003907:Dexamethasone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020743:rhoB GTP-Binding Protein
keywords: RhoB; cell survival; dexamethasone; hypoxia