The mechanisms and significance of up‐regulation of RhoB expression by hypoxia and glucocorticoid in rat lung and A549 cells

• Published in: Journal of cellular and molecular medicine Vol. 20; no. 7; pp. 1276 - 1286
• Main Authors: Huang, Gao‐Xiang, Pan, Xiao‐Yu, Jin, Yi‐Duo, Wang, Yan, Song, Xiao‐Lian, Wang, Chang‐Hui, Li, Yi‐Dong, Lu, Jian
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2016; John Wiley and Sons Inc
• Subjects: A549 Cells; Adaptation; Animals; Antineoplastic Agents - pharmacology; Cancer therapies; Cell adhesion & migration; Cell growth; Cell Hypoxia - drug effects; Cell Hypoxia - genetics; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell survival; Cell Survival - drug effects; Chemotherapy; Cytoskeleton; Dexamethasone; Dexamethasone - pharmacology; Drug Resistance, Neoplasm - drug effects; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Glucocorticoids; Glucocorticoids - pharmacology; Growth factors; Guanosine; Guanosine triphosphate; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; Laboratory animals; Lung - drug effects; Lung - metabolism; Lung cancer; Lung carcinoma; Medical research; Metastasis; Models, Biological; Original; p38 Mitogen-Activated Protein Kinases - metabolism; Paclitaxel; Pulmonary arteries; Radiation therapy; Rats, Sprague-Dawley; RhoB; rhoB GTP-Binding Protein - genetics; rhoB GTP-Binding Protein - metabolism; RNA Stability - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; siRNA; Steroids; Transcription factors; Tumors; Up-regulation; Up-Regulation - drug effects; St Louis Missouri; United States > US; China; dexamethasone; hypoxia; cell survival; RhoB
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.12809

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.