GOLPH3 promotes glioblastoma cell migration and invasion via the mTOR‐YB1 pathway in vitro

Abstract

The identification of genes involved in carcinogenesis and tumor progression is of great interest, since these genes might be possible as candidates for new tumor targeted therapy strategies. Our previous study shows that Golgi phosphoprotein 3 (GOLPH3) is involved in glioma cell migration and invasion, the critical characteristics of malignant gliomas. In this study, we explored the mechanism of GOLPH3 affecting cell migration and invasion and found that GOLPH3 promotes glioblastoma (GBM) cell migration and invasion via the mammalian target of rapamycin(mTOR)-Y-box binding protein-1 (YB1) pathway in vitro. Both the protein levels of GOLPH3 and YB1 were up-regulated in human glioma tissues and they exhibited direct correlation with each other. In addition, down-regulation of GOLPH3 inhibited glioma cell migration and invasion, while over-expression of GOLPH3 enhanced them. Meanwhile, GOLPH3 down-regulation led to a significant decrease of YB1 level as well as mTOR activity, both required for glioma cell migration and invasion. On the contrary, YB1 level and mTOR activity increased after GOLPH3 over-expression. YB1 down-regulation or mTOR ATP site inhibitor INK128 treatment inhibited cell migration and invasion, similar to the effect of GOLPH3 down-regulation. Furthermore, over-expression of GOLPH3 induced glioma cell migration and invasion was blocked by INK128 and YB1 down-regulation. Taken together, these results show that GOLPH3 promotes glioblastoma cell migration and invasion via the mTOR-YB1pathway, indicating that GOLPH3-mTOR-YB1 pathway might be a new therapeutic target for glioma treatment.

Golgi Phosphoprotein 3 Promotes Wls Recycling and Wnt Secretion in Glioma Progression

“…Notably, GOLPH3 shRNA did not affect the protein level of GOLPH3 paralogue GOLPH3L [37] (sFig. 1B-1D) and could be rescued by GOLPH3 Res (shRNA-resistant mutant of GOLPH3), indicating the specificity of GOLPH3 shRNA [19,21]. Furthermore, the high down-regulation efficiency of GOLPH3 shRNA was also confirmed by immunofluoresence assay (see online suppl.…”

“…Studies about the mechanism of GOLPH3 in cancer biology are mainly focused on the following signal pathways, such as mTOR-YB1, GSK3β-FOXO1 and AKT-mTOR, but rarely attach importance to its biological roles of golgi trafficking, receptor recycling and glycosylation in cancers [12,17,19]. It is reported that GOLPH3 interacts with and mediates the golgi localization of POMGnT1 [42], a mammalian glycosyltransferase, which promotes glioblastoma progression [43].…”

mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors

“…Unless otherwise indicated, drug concentrations were as follows: vorinostat (2μM), romidepsin (1nM), panobinostat (20nM), sapanisertib (200nM for all cell lines except 90-8TLs, where sapanisertib was used at 100nM), auranofin (750nM), buthionine sulfoximine (200 μM). The concentration of sapanisertib (200nM) was chosen based on previously published studies (23,56,57). 100nM was used in 90-8TLs for historical reasons but 200nM produces the same results.…”

GOLPH3 Links the Golgi, DNA Damage, and Cancer

“…Evidence of transformation by overexpression of GOLPH3 has been reported in MDA-MB-231 and MCF7 breast cancer cell lines (9–11), and U251 and U87 glioblastoma cell lines (12, 13). Frequent overexpression of GOLPH3 and correlation with poor prognosis have been reported in multiple tumor types including 58–72% of non-small cell lung cancers (14, 15), 52% of breast cancers (11), 70% of prostate cancers (16), 73% of pancreatic ductal adenocarcinomas (17), 65% of hepatocellular carcinomas (18, 19), 55–58% of gastric cancers (20, 21), 53% of renal cell carcinomas (22), 41–53% of glioblastomas (12, 23, 24), 49% of esophageal squamous carcinomas (25), and 45% of ovarian carcinomas (26, 27). Overexpression of GOLPH3 occurs frequently in rhabdomyosarcoma, and knockdown of GOLPH3 in rhabdomyosarcoma cell lines impairs cell proliferation (28).…”