14-3-3σ attenuates RhoGDI2-induced cisplatin resistance through activation of Erk and p38 in gastric cancer cells

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.

RhoGDI2 promotes epithelial-mesenchymal transition via induction of Snail in gastric cancer cells

“…We previously showed that RhoGDI2 protects gastric cancer cells against apoptosis induced by various chemotherapeutic agents [33-35], as well as promotes gastric cancer cell invasion. Furthermore, Snail mediates chemoresistance in many cancer cell types [36-39].…”

TES inhibits colorectal cancer progression through activation of p38

“…Furthermore, p38 was found to be a marker for tumor dormancy and an inhibitor of self-renewal in several cancers, including melanoma as well as breast, prostate, and colorectal carcinomas [58]. Inhibition of p38 could enhance the chemo resistance of gastric cancer, which shares chemotherapy regimens with colorectal cancer [59]. Conversely, other reports have suggested that p38 is involved in cell survival and increased invasion in several advanced tumor types, including lung and prostate cancers [60–62], suggesting that increased p38-MAPK activity is correlated with poor prognosis.…”

“…A percentage of the cleared area at 36 h compared with 0 h after wounding was measured using Image-Pro Plus v6.2 software. For the uncoated Transwell ® assay, as described in earlier studies [59, 74, 79–81], the uncoated Transwell ® filter inserts with eight micron pores (BD Biosciences, Bedford, MA, USA) in 24-well cell culture plates were used. Cell invasion properties were measured by the Transwell ® Invasion assay (BD Biosciences, Bedford, MA, USA) along with chambers consisting of precoated Matrigel membrane Transwell ® filter inserts with eight micron pores in 24-well cell culture plates.…”

Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma

“…Excitingly, while this work was in preparation two other reports demonstrated that BRD4 inhibition with JQ1 can inhibit medulloblastoma cell growth in vitro and in vivo[25, 26]. Henssen et al showed that JQ1 reduces cell viability and proliferation and induces apoptosis in human medulloblastoma cell lines in vitro and in vivo [25]. Bandopadhayay et al also showed that JQ1 reduced cell proliferation and induced apoptosis in MYC-amplified medulloblastoma in vitro and prolonged survival in xenograft models[26].…”

“…Several hematologic malignancies, the highly malignant NUT midline carcinoma and the pediatric adrenal gland tumor neuroblastoma are responsive to BRD4 inhibition in vitro and in mouse models [16, 17, 22–24]. Furthermore two recent reports also show the utility of BRD4 inhibition in medulloblastoma[25, 26]. …”