Metabolic alterations induced by attenuated Zika virus in glioblastoma cells

Abstract

Background: Zika virus (ZIKV) has recently become a major matter of concern since its association with microcephaly cases in newborns was determined. From then on, ZIKV has been untiringly studied, and several scientific data have shown the virus' tropism to neural cells. Previous studies have proposed that ZIKV induced glioblastoma cells death, suggesting that ZIKV and ZIKV-associated molecules might induce intracellular biochemical alterations, and thereby be alternatives for neural cancer management. In this sense, the present contribution presents a prospective approach for glioblastomas management: producing a ZIKV-based therapy that stimulates glioblastoma control. We developed an attenuated ZIKV prototype based on bacterial outer membrane vesicles (OMV). The attenuated ZIKV was applied on glioblastoma cells, where cytopathic and cytostatic effects were evaluated. Glioblastoma cells, with and without treatment, were submitted to mass spectrometry analysis. Results: Microscopic analysis showed cytopathic effects induced by ZIKV prototype on glioblastoma cells after 24 and 48 h post-treatment. DNA fragmentation assay and TNF-alpha expression were indicative that ZVp induced cell damage and death. The metabolomics investigation elected 5 different biomarkers that might be associated with cell cytopathic effects, highlighting intracellular biochemical modifications induced by the attenuated ZIKV. The remarkable evidence of cell death in glioblastoma stimulated further studies that rendered a preliminary screening with other tumor cell lineages, though anti-proliferative activity test. Among the 11 tumors evaluated, prostate and ovarian tumors were the most affected by ZIKV prototype, and other 6 cell lines also presented cytostatic effects. Conclusions: Results ultimately demonstrated that this prototype not only emerges as a potential alternative for glioblastoma management, but may also be an important tool against other important tumors.

Molecular signatures associated with prostate cancer cell line (PC-3) exposure to inactivated Zika virus

“…Anionic lipids such as PA and lysoPA favor membrane curvature by the action of flipases, and this rearrangement may promote better interaction of membrane phospholipids with flavivirus’ molecules 36 . Phosphatidylinositols in particular had their association with ZIKV previously reported in metabolomic studies 9,16 , corroborating to our findings. When evaluating the cytostatic impact of inactivated ZIKV on glioblastoma cells, Dabaja et al .…”

“…It was possible to correlate biomarkers’ function with the recent finds on the antiproliferative effect of Zika virus on prostate cancer cell 16 . Some molecules, identified on Table 1, are involved on cell mechanisms impaired during viral exposure, while others suggest altered pathways that might lead to prostate cancer cell death.…”

“…When evaluating the cytostatic impact of inactivated ZIKV on glioblastoma cells, Dabaja et al . (2018) observed PI and phosphatidylinositol phosphate (PIP) as biomarkers 16 . In addition, Melo et al .…”

“…Given the ZIKV tropism to various cell types, and its ability of interrupting cell growth, a hypothesis was raised about its oncolytic potential. In vitro 15,16 and in vivo 17 experiments were conducted to confirm the antiproliferative activity of Zika against glioblastoma tumor cells. Zhu et al .…”

“…(2018) evaluated metabolic alterations in glioblastoma cells induced by a ZIKV prototype (ZVp), which also demonstrated cytopathic effects. This prototype based on inactivated ZIKV particles fused with Outer Membrane Vesicles (OMV) from Neisseria meningitidis demonstrated significant immune response and great potential for tumor management 16,19 . Additionally to the cytopathic effect demonstrated in glioblastoma cells, ZVp has also shown tropism and antiproliferative effects against the PC-3 androgen-independent human prostate cancer cell line 16 , whose mechanisms are yet to be elucidated.…”