Abstract
Rho GDP dissociation inhibitor 2 (RhoGDI2) promotes tumor growth and malignant progression and enhances chemoresistance of gastric cancer. Recently, we noted an inverse correlation between RhoGDI2 and 14-3-3σ expression, which suggests that 14-3-3σ is a target of gastric cancer metastasis and the chemoresistance-promoting effect of RhoGDI2. Herein, we evaluated whether 14-3-3σ is regulated by RhoGDI2 and is functionally important for the RhoGDI2-induced cisplatin resistance of gastric cancer cells. We used highly metastatic and cisplatin-resistant RhoGDI2-overexpressing SNU-484 cells and observed decreased 14-3-3σ mRNA and protein expression. Depletion of 14-3-3σ in SNU-484 control cells enhanced cisplatin resistance, whereas restoration of 14-3-3σ in RhoGDI2-overexpressing SNU-484 cells impaired cisplatin resistance in vitro and in vivo. We also found that the phosphorylation levels of Erk and p38 kinases significantly decreased in RhoGDI2-overexpressing SNU-484 cells and recovered after 14-3-3σ expression, and that decreased activities of these kinases were critical for RhoGDI2-induced cisplatin resistance. In conclusion, 14-3-3σ is a RhoGDI2-regulated gene that appears to be important for suppressing the chemoresistance of gastric cancer cells.
Highlights
The incidence and mortality of gastric cancer have steadily declined in recent decades, it remains the fourth most common type of cancer and the second leading cause of cancer mortality worldwide [1]
Ronneburg et al demonstrated that RhoGDI1 may sensitize invasive breast cancer to treatment with CMF, and higher RhoGDI1 expression tends to be correlated with a better clinical outcome [30]
In contrast to RhoGDI1, several groups have focused their research on elucidating the explicit mechanisms by which Rho GDP dissociation inhibitor 2 (RhoGDI2) regulates aggressive features of cancer cells, motility, invasiveness, and metastasis
Summary
The incidence and mortality of gastric cancer have steadily declined in recent decades, it remains the fourth most common type of cancer and the second leading cause of cancer mortality worldwide [1]. Cancer treatment is limited by the different efficacies of chemotherapeutic regimens, diverse disease states of patients and response rate to drugs, drug-related side-effects, acquisition of drug resistance, and cancer recurrence with metastasis [8,9,10,11] To this end, the targeted approaches that focus on drug resistance-associated molecules are required to improve the efficacy of chemotherapy against advanced gastric cancers. RhoGDI2 mRNA expression is significantly higher in ovarian adenocarcinomas than in benign adenomas [19] Consistent with this finding, RhoGDI2 is overexpressed in human breast cancer cell lines, and it increases cancer cell invasiveness and motility in vitro [20]. The restoration of 14-3-3σ is associated with impaired RhoGDI2-induced chemoresistance of gastric cancer cells through the activation of p38 and Erk
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