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.

Clinical value of miR-182-5p in lung squamous cell carcinoma: a study combining data from TCGA, GEO, and RT-qPCR validation

“…RHOB belongs to the Ras homolog gene family. RHOB plays a role in cell proliferation and survival [ 55 ]. RHOB also inhibits tumor growth.…”

PTGDR gene expression and response to dexamethasone treatment in an in vitro model

“…A549 cells (human adenocarcinoma alveolar basal epithelial cells, type II) were kindly provided by Dr Odero (CIMA, University of Navarra) and maintained in RPMI with 10% Fetal Bovine Serum (FBS) (Gibco, Invitrogen-Life Technologies, MA, USA) at 37°C in a humidified atmosphere with 5% CO 2 . To perform luciferase and expression experiments, cells were grown in RPMI supplemented with 10% Charcoal Stripped FBS (Gibco, Invitrogen-Life Technologies, MA, USA) to avoid possible interference with serum steroids [ 23 , 24 ].…”

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia

“…Both hypoxia and dexamethasone independently induced and co-regulated expression and activation of the guanosine triphosphate (GTP)-binding protein RhoB, an important stress sensor which contributes to the regulation of cytoskeletal organization, cell proliferation and survival [ 63 ]. HIF-1α, JNK and ERK were also shown to be involved in up-regulation of RhoB in hypoxia [ 64 ].…”