Inhibition of glioblastoma malignancy by Lgl1

Abstract

lethal giant larvae (lgl) was first identified as a tumor suppressor in Drosophila, where its loss repressed the differentiation and promoted the invasion of neuroblasts, the Drosophila equivalent of the neural stem cell. Recently we have shown that a human homolog of Lgl, Lgl1 (LLGL1), is constitutively phosphorylated and inactivated in glioblastoma cells; this occurs as a downstream consequence of PTEN loss, one of the most frequent genetic events in glioblastoma. Here we have investigated the consequences of this loss of functional Lgl1 in glioblastoma in vivo. We used a doxycycline-inducible system to express a non-phosphorylatable, constitutively active version of Lgl1 (Lgl3SA) in either a glioblastoma cell line or primary glioblastoma cells isolated under neural stem cell culture conditions from patients. In both types of cells, expression of Lgl3SA, but not wild type Lgl1, inhibited cell motility in vitro. Induction of Lgl3SA in intracerebral xenografts markedly reduced the in vivo invasion of primary glioblastoma cells. Lgl3SA expression also induced the differentiation of glioblastoma cells in vitro and in vivo along the neuronal lineage. Thus the central features of Lgl function as a tumor suppressor in Drosophila are conserved in human glioblastoma.

PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion

“…Immunohistochemistry was done as described previously [21]. Antigen retrieval was performed in citrate buffer, pH 6.0 (Vector, Burlingame, CA, USA) in a decloaking chamber using the instrument's default program (Biocare Medical, CA, USA).…”

PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion

“…PriGO cell culture cells were established as xenografts in SCID/Beige mice (Charles River Laboratories, MA, USA) as described previously [21]. 1x10 6 cells in 10μL Neurobasal A medium were injected intracranially using a Hamilton 700 series syringe (Reno, NV, USA) in a stereotactic system.…”

Cancer Drug Development Using Drosophila as an in vivo Tool: From Bedside to Bench and Back

“…The utility of the model in combination therapy and drug uptake/bioavailability is also discussed. Brain cancer PDGF, EGFR, PI3K, Notch [106][107][108][109] Medullary thyroid carcinoma RET, Ras, EGFR, ERK [30,32,34,110] Tuberous sclerosis TSC-1, TSC-2 [111,112] Colorectal cancer Wnt, EGFR, Ras [40,113,114] Prostate cancer MRGBP, CNPY2, MEP1A [115] Ovarian cancer YAP/Hippo [116] Skin cancer Hh/Ptc [117] Drosophila in Cancer Drug Discovery…”