Vestal, D. J. | bioRxiv Science

bioRxiv2024

The large GTPase Guanylate-Binding Protein-1 (GBP-1) promotes mitochondrial fission in glioblastoma.

Glioblastomas (aka Glioblastoma multiforme (GBMs)) are the most deadly of the adult brain tumors. Even with aggressive treatment, the prognosis is extremely poor. The large GTPase Guanylate-Binding Protein-1 (GBP-1) contributes to the poor prognosis of GBM by promoting migration and invasion. GBP-1 is substantially localized to the cytosolic side of the outer membrane of mitochondria in GBM cells. Because mitochondrial dynamics, particularly mitochondrial fission, can drive cell migration and invasion, the potential interactions between GBP-1 and mitochondrial dynamin-related protein 1 (Drp1) were explored. Drp1 is the major driver of mitochondrial fission. While GBP-1 and Drp1 both had punctate distributions within the cytoplasm and localized to regions of the cytoplasmic side of the plasma membrane of GBM cells, the proteins were only molecularly co-localized at the mitochondria. Subcellular fractionation showed that the presence of elevated GBP-1 promoted the movement of Drp1 from the cytosol to the mitochondria. Migration of U251 cells treated with the Drp1 inhibitor, Mdivi-1, was less inhibited in the cells with elevated GBP-1. Elevated GBP-1 in GBM cells resulted in shorter and wider mitochondria, most likely from mitochondrial fission. Mitochondrial fission can drive a number of important cellular processes, including cell migration, invasion, and metastasis. Simple SummaryGlioblastomas are the most common and most aggressive adult brain tumors arising from astrocytes. Up to 60% of glioblastomas are promoted by either amplification and/or mutation of the Epidermal Growth Factor Receptor (EGFR). The large GTPase Guanylate-Binding Protein-1 (GBP-1) is one of the most robustly induced proteins following EGFR signaling in glioblastomas. How GBP-1 promotes tumor progression in glioblastomas is still under investigation. This study shows that GBP-1 promotes tumor progression by associating with Drp1 at glioblastoma mitochondria and enhancing their fission. Specifically, increased mitochondrial fission can promote tumor cell migration, invasion, and metastasis.

cancer biology↗

bioRxiv2019

The large GTPase, mGBP-2, inhibits Triple-Negative Breast Cancer cell migration, but not proliferation

Breast cancer is the most common cancer in women. Despite advances in early detection and treatment, it is predicted that over 40,000 women will die of breast cancer in 2019. This number of women is still too high. To lower this number, more information about the molecular players in breast cancer are needed. Several members of the Guanylate-Binding Proteins (GBPs) have been correlated with better prognosis in breast cancer. In this study, we asked if the expression of GBP-2 in breast cancer merely provided a biomarker for improved prognosis or whether it actually contributed to improving outcome. Specifically, we asked whether murine GBP-2 exhibited cell autonomous behavior that altered breast cancer cells in a manner predicted to improve prognosis. To answer this, the 4T1 model of murine Triple-Negative Breast Cancer was used. 4T1 cells themselves are highly aggressive and highly metastatic, while 67NR cells, isolated from the same tumor, do not leave the primary site. mGBP-2 did not alter cell proliferation in these two cell lines, but mGBP-2 expression inversely correlated with migration. More specifically, mGBP-2 inhibits cell migration and invadopodia formation by inhibiting the activation of Rac1, while promoting the activation of CDC42 and RhoA. Together these data demonstrate that mGBP-2 is responsible for cell autonomous activities that make breast cancer cells less aggressive.

cancer biology↗