Abstract. Cdc42, a Rho GTPase family member, is involved in cell transformation, proliferation, survival, invasion and metastasis of human cancer cells. Overexpression of Cdc42 has been reported in several types of human cancer. However, the underlying mechanisms are not well understood. The present study showed that Cdc42 was overexpressed in 80 of 110 primary lung cancer patients, and overexpression of Cdc42 was significantly associated with high TNM stage and lymph node metastasis. Moreover, RNAi-mediated suppression of Cdc42 expression reduced actin filopodia formation, migration and invasion potential of a highly metastatic lung cancer cell line, 801D. In parallel, 801D cells were treated with curcumin and the effect on the expression of the Cdc42 gene at the transcriptional and translational levels was analyzed by RT-PCR and Western blotting. Curcumin inhibited cell migration, invasion and downregulated Cdc42 gene and Cdc42-related target gene expression in 801D cells. It also induced rearrangements of the actin cytoskeleton. These effects mimicked those of Cdc42 knockdown. Furthermore, xenograft experiments confirmed the suppression of tumor growth and invasion in vivo, which was due to the effect of curcumin and the inhibition of Cdc42 by curcumin. Our results showing the downregulation of Cdc42 expression by curcumin in lung cancer cells taken together with the clinical data suggest a potential therapeutic role for curcumin in inducing Cdc42-mediated inhibition of invasion of lung cancer cells.
Abstract. Rac1, an intracellular signal transducer, regulates a variety of cell functions, including the organization of the cytoskeleton, cell migration, and invasion. Overexpression of Rac1 has been reported in several human cancers. However, the underlying mechanisms are not well understood. In the present study, we evaluated the possibility of Rac1 as an appropriate molecular target for cancer gene therapy. The expression of Rac1 in 150 primary non-small cell lung cancer tissues (NSCLC) and 30 normal paraneoplastic lung tissues was determined by immunohistochemical staining, and the correlation of Rac1 overexpression with clinicopathological factors was evaluated. Overexpression of Rac1 was detected in 94 of 150 lung cancer specimens, the incidence rate being higher than that in normal lung tissue specimens. In addition, overexpression of Rac1 was also associated with poor differentiation, high TNM stage, and lymph node metastasis in NSCLC patients. Moreover, RNAi-mediated suppression of Rac1 expression reduced lamellipodia formation, migration and invasion potential of a lung cancer cell carcinoma cell line, 801D. Down-regulation of Rac1 expression also reduced the expression of Pak1. NSC23766, an inhibitor of Rac1 activity, could also inhibit lung cancer cell migration, invasion and induce rearrangements of the actin cytoskeleton. Furthermore, the suppression of Rac1 expression also sensitized cells to antitumor drugs. These results indicate that the overexpression of Rac1 is tightly associated with an aggressive phenotype of lung cancer cells. Therefore, we proposed that Rac1 could be a potential molecular target of gene therapy by RNAi-targeting in lung cancer cells.
Background: Diabetes Mellitus (DM) accelerates progress of lung cancer. Hyperglycemia, a critical feature of DM, promotes lung cancer metastasis. Mogroside V is a triterpenoid glycoside from Siraitia grosvenorii. Interestingly, mogroside V not only plays an anti-diabetic role, but also has anti-tumor effects. Objective: In this study, we investigated the metastatic efficiency of mogroside V in lung cancer cells cultured in hyperglycemia. Methods: Two lung cancer cell lines-A549 and H1299 were cultured in normoglycemia (5.5mM glucose) and hyperglycemia (25mM glucose). Cellular proliferation was tested by MTT, invasion was examined by transwell assay, migration was measured by wound healing assay, cytoskeleton was stained by Phalloidin-TRITC and the expressions of EMT markers and Rho-GTPase family protein were detected by western blot. Results: Hyperglycemia promoted the invasion and migration of A549 and H1299 cells compared with normoglycemia. Mogroside V inhibited the hyperglycemia-induced invasion and migration. Hyperglycemia promoted epithelial-mesenchymal transition (EMT), while mogroside V could reverse this process through up-regulating E-Cadherin expression and down-regulating N-Cadherin, Vimentin, Snail expressions. Furthermore, mogroside V fractured microfilaments and reduced Rho A, Rac1, Cdc42 and p-PAK1 expressions under hyperglycemic conditions. Conclusion: These results suggest that mogroside V inhibits hyperglycemia-induced lung cancer cells migration and invasion through reversing EMT and damaging cytoskeleton.
To utilize single-photon emission computed tomography/computed tomography (SPECT/CT) scanning to investigate the usefulness of nerve root compression (NRC) and radioactive cold zone lesions (RCZLs) for predicting poor therapeutic efficacy of strontium-89 chloride (Sr-89) in patients with bone metastasis. Patients with bone metastatic neoplasms who had undergone baseline bone SPECT/CT scanning before Sr-89 therapy (148 MBq Sr-89 chloride by an intravenous injection for each patient) between July 2011 and July 2018 were included. Bone SPECT/CT images were assessed by two readers independently. Associations between imaging features and therapeutic efficacy were obtained via multivariate logistic regression analysis. Of 231 patients analyzed, 50 (21.6%) had NRC at baseline. Of 31 patients who experienced poor therapeutic efficacy, 29 (93.5%) had NRC. In multivariate logistic regression analysis baseline NRC independently predicted poor therapeutic efficacy. The sensitivity of NRC for predicting poor therapeutic efficacy was 93.5%, specificity was 89.5%, positive predictive value was 58.0%, and negative predictive value was 98.9%. RCZLs were detected in17 patients (7.4%), of whom 14 experienced poor Sr-89 therapeutic efficacy. The sensitivity of the presence of RCZLs for predicting poor therapeutic efficacy was 45.2%, specificity was 98.5%, positive predictive value was 82.4%, and negative predictive value was 92.1%. After adjusting for age, bone metabolism and lesion type, the significant independent predictors of poor Sr-89 therapeutic efficacy were presence of NRC (p < 0.001) and RCZL (p = 0.001). NRC and RCZL on baseline bone SPECT/CT are reliable independent predictors of poor Sr-89 therapeutic efficacy in patients with bone metastasis. These associations may facilitate the administration of more effective therapeutic interventions.
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