HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway

Abstract

Glioblastoma is the most common malignant tumor in central nervous system (CNS), and it is still insurmountable and has a poor prognosis. The proliferation and survival mechanism of glioma cells needs to be explored further for the development of glioma treatment. Hematopoietic-substrate-1 associated protein X-1 (HAX-1) has been reported as an anti-apoptosis protein that plays an important role in several malignant tumors. However, the effect and mechanism of HAX-1 in glioblastomas remains unknown. This study aimed to investigate the effect of HAX-1 in glioblastoma cells and explore the mechanism. The results of clone formation and Edu proliferation assay showed slower multiplication in HAX-1 knock-out cells. Flow cytometry showed cell cycle arrest mainly in G0/G1 phase. Apoptosis due to oxidative stress was increased after HAX-1 was knocked out. Western-blot assay exhibited that the levels of p21, Bax, and p53 proteins were significantly raised, and that the activation of the caspase cascade was enhanced in the absence of HAX-1. The degradation rate and ubiquitination of p53 declined because of the decrease in phosphorylation of proteins MDM2 and Akt1. Co-immunoprecipitation (Co-IP) and immunefluorescent co-localization assays were performed to test the influence of HAX-1 on the interaction between Akt1 and Hsp90, which is crucial for the activity of Akt1. In conclusion, this novel study suggested that HAX-1 could affect the Akt1 pathway through Hsp90. The knock-out of HAX-1 leads to the inactivity of the Ak1t/MDM2 axis, which leads to increased levels of p53, and finally generates cell cycle arrest and results in the apoptosis of glioblastoma cells.

Hematopoietic-substrate-1 associated protein X-1 (HAX-1) regulates liver cancer cells growth, metastasis, and angiogenesis through Akt

“…By reviewing previous studies, we found that HAX-1 regulated cell growth and metastasis via JAK/STAT and Akt/mTOR signaling pathways. 23,24 In addition, JAK/STAT and Akt/mTOR are ubiquitously expressed, and their activation is also one of the factors causing malignant proliferation and metastasis of liver cancer cells. [25][26][27] The results of this study showed that silencing or overexpression of HAX-1 had no significant effect on the JAK/STAT pathway for SK-Hep1 and SUN387 cells.…”

Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis

“…FasL and Trail can bind to their receptors in turn causing caspase cascades and propagating the process of cellular apoptosis (Nagata, 1997; Vasaikar et al, 2015). The P53 protein regulates cellular apoptosis through multiple pathways, including activating the expression of pro-apoptotic genes and promoting the formation of apoptosome (Wawryk-Gawda et al, 2014; Deng et al, 2017). To identify genes incorporated in our model, we utilized qRT-PCR to define that Bim, P53, Trial, Bcl-2 and Mcl-1—but not FasL— as novel targets regulated by nuclear FOXO3 at the transcriptional level.…”

HAX1 enhances the survival and metastasis of non‐small cell lung cancer through the AKT/mTOR and MDM2/p53 signaling pathway

“…HAX1 suppresses NSCLC cell apoptosis through inhibiting AKT/mTOR signal pathway A recent study reported that HAX1 prevents glioblastoma cells from apoptosis through the Akt1 pathway, 15 and it has also been reported that the AKT/mTOR signal pathway plays an important role in NSCLC. AKT/mTOR signal pathway induces gefitinib-resistant of NSCLC.…”

“…As a downstream of AKT, MDM2/p53 signal pathway has been reported to play an important role in glioblastoma cells and endothelial progenitor cells. 15 We further investigated whether the MDM2/p53 signal pathway participates in NSCLC cells transfected with si-HAX1. We observed the protein level of p-MDM2 was reduced and p53 was increased in A549 and H1299 cells after si-HAX1 transfection (Fig 5a,b).…”