Open AccessThe mechanisms and significance of up‐regulation of RhoB expression by hypoxia and glucocorticoid in rat lung and A549 cells
Author(s) -
Huang GaoXiang,
Pan XiaoYu,
Jin YiDuo,
Wang Yan,
Song XiaoLian,
Wang ChangHui,
Li YiDong,
Lu Jian
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12809
Subject(s) - rhob , a549 cell , biology , cancer research , hypoxia (environmental) , gene knockdown , kinase , microbiology and biotechnology , signal transduction , cell , rhoa , chemistry , apoptosis , biochemistry , organic chemistry , oxygen
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 si RNA 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.