HIV-1 Envelope Protein gp120 Promotes Proliferation and the Activation of Glycolysis in Glioma Cell

Abstract

Patients infected with human immunodeficiency virus (HIV) are more prone to developing cancers, including glioblastomas (GBMs). The median survival for HIV positive GBM patients is significantly shorter than for those who are uninfected, despite the fact that they receive the same treatments. The nature of the GBM–HIV association remains poorly understood. In this study, we analyzed the effect of the HIV envelope glycoprotein gp120 on GBM cell proliferation. Specifically, we performed cell cycle, western blot, protein synthesis and metabolomics analysis as well as ATP production and oxygen consumption assays to evaluate proliferation and metabolic pathways in primary human glioma cell line, U87, A172 cells and in the HIVgp120tg/GL261 mouse model. Glioma cells treated with gp120 (100 ng/mL for 7–10 days) showed higher proliferation rates and upregulation in the expression of enolase 2, hexokinase and glyceraldehyde-3-phosphate dehydrogenase when compared to untreated cells. Furthermore, we detected an increase in the activity of pyruvate kinase and a higher glycolytic index in gp120 treated cells. Gp120 treated GBM cells also showed heightened lipid and protein synthesis. Overall, we demonstrate that in glioma cells, the HIV envelope glycoprotein promotes proliferation and activation of glycolysis resulting in increased protein and lipid synthesis.

Oncogenic Effects of HIV-1 Proteins, Mechanisms Behind

“…This interaction promotes proliferation, migration, survival and stimulates glycolysis in glioma cell lines and tumor growth in animal models [ 127 ]. Increased glycolysis, also known as the Warburg effect characteristic of malignancy [ 128 ], results in increased protein and lipid synthesis, and promotes uncontrolled propagation (both proliferation and invasion) of tumor cells, as it provides them with glycolytic intermediary precursors required for the synthesis of DNA, proteins and lipids [ 127 , 129 ]. As Tat, gp120 induces EMT and cell migration through the TGF-B1 and MAPK signaling pathways [ 115 , 130 ].…”

HIV-1 Reverse Transcriptase Promotes Tumor Growth and Metastasis Formation via ROS-Dependent Upregulation of Twist

“…Mechanistically, Nef inhibits the apoptotic function of p53; it decreases the half-life of p53 and interferes with p53 DNA binding activity and transcriptional activation [12]. HIV-1 glycoprotein gp120 stimulates glycolysis [13]. Increased glycolysis, also known as the Warburg effect, is a well-known feature of the majority of tumors that supports unconstrained proliferation and invasion of tumor cells [14, 15].…”

“…Increased glycolysis, also known as the Warburg effect, is a well-known feature of the majority of tumors that supports unconstrained proliferation and invasion of tumor cells [14, 15]. Indeed, gp120 has been shown to promote proliferation, migration, and survival of tumor cells when expressed on the viral particles, on the surface of infected cells, or as a virus-free soluble protein [13, 16]. Expression of HIV-1 Tat has been associated with the development of B-cell lymphomas [17, 18] and colorectal [19] and HPV-associated cancers [20].…”

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

“…29 The clonogenic power and cell-cycle progression of glioma cells were also mediated by misregulation of HKII. 27,30 Regarding autophagic death, HKII was confirmed its relevance with glioma cells treated by RSL3, a novel compound of small molecules targeting glutathione peroxidase 4 (GPX4). 31 Subsequent functional investigation has been carried out for roles of HKII in glioma, which may emerge as a promising therapeutic target for glioma treatment.…”

“…26 Conversely, a higher glycolytic index along with activated procedures of lipid and protein synthesis was induced by HKII overexpression. 27 Nie et al 28 also reported that the elevated HKII contributed to an increase in glucose uptake and lactate production in glioma cells with IDH1R 132 H mutation. Further in vitro experiments illustrated that HKII was significantly upregulated in gliomas and related to proliferation, invasion, apoptosis, and angiogenesis.…”