Bex2 Controls Proliferation of Human Glioblastoma Cells Through NF-κB Signaling Pathway

Abstract

Glioblastoma is the most common and fatal human brain malignancy in adults with highly proliferative capacity. Despite advances in surgery and adjuvant therapy, the median survival of patients has changed little over recent decades. Identifying molecules critical for glioma development is significant for devising effective targeted therapy. We previously reported that Bex2, a member of the brain expressed X-linked gene family, promoted the progression of glioma by promoting cell proliferation. In the present study, we investigated the main mechanism of Bex2 promoting the proliferation of glioblastoma cells. We found that Bex2 downregulation inhibited glioma cell proliferation and the expression of NF-κB p65, but Bex2 overexpression promoted them. Similarly, the proliferation of glioma cells was inhibited by p65 downregulation but increased by p65 overexpression. In addition, Bex2 overexpression-induced cell proliferation was abolished by p65 downregulation. Furthermore, Bex2 with nuclear localization signal deleted no longer promoted p65 expression. In conclusion, this study demonstrates that Bex2 promotes proliferation of human glioblastoma cells via NF-κB signaling pathway and Bex2 nuclear location is critical for p65 expression.

Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma

“…P53 is a well-known pro-apoptotic molecule, and others have seen increases in apoptotic markers 17 and decreases in proliferation in GBM upon downregulation of NF-ĸB. 18,19 GBM stem cells from patient samples which express FACT show an increase in apoptosis upon treatment with CBL0137. 20 These results further suggest that glioma is responsive to CBL0137 and that CBL0137 would be a beneficial treatment.…”

BEX2 promotes tumor proliferation in colorectal cancer

“…However, BEX2 is highly expressed in a subset of estrogen receptor-positive breast cancers 10 and glioblastoma 11 and plays a key role in promoting cell survival and growth in breast cancer cells. The BEX protein family has been reported to contain long regions of intrinsic disorder that may form signaling hubs, and the hubs formed by intrinsically disordered proteins play important roles in cellular differentiation and cancer 6.…”

“…BEX2 is highly expressed in the embryonic brain and can interact with transcriptional factor LMO2 to regulate transcriptional activity 8. In addition, BEX2 has been reported to be involved in tumor development in several types of cancer, such as glioblastoma, glioma and breast cancer 9-11. Naderi et al found that BEX2 was up-regulated in a subset of primary breast cancers and that down-regulation of BEX2 induced G1-phase arrest in breast cancer cell lines 10.…”

“…Naderi et al found that BEX2 was up-regulated in a subset of primary breast cancers and that down-regulation of BEX2 induced G1-phase arrest in breast cancer cell lines 10. BEX2 is also highly expressed in glioblastomas and promotes cell proliferation and survival by mediating nuclear factor-kappa B activity 11. However, other studies have obtained opposite findings, showing that BEX2 inhibits cell proliferation.…”

Brain-Expressed X-linked (BEX) proteins in human cancers

“…However, another report examining 32 gliomas vs 15 nontumor tissues showed that BEX2 expression was 2.73 fold upregulated in glioma [26]. Selective depletion of BEX2 expression in glioma cells led to reduction of U251 cell proliferation, while 8 overexpression resulted in elevated cell proliferation [26,80]. Similar to the breast cancer cells, BEX2 expression enhanced p65 expression as well as activation of NF-κB pathway in the U251 cells.…”