ARL4C stabilized by AKT/mTOR pathway promotes the invasion of PTEN-deficient primary human glioblastoma.

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency in primary human glioblastoma (GBM) is associated with increased invasiveness and poor prognosis with unknown mechanisms. Therefore, how loss of PTEN promotes GBM progression remains to be elucidated. Herein, we identified that ADP-ribosylation factor like-4C (ARL4C) was highly expressed in PTEN-deficient human GBM cells and tissues. Mechanistically, loss of PTEN stabilized ARL4C protein due to AKT/mTOR pathway-mediated inhibition of ARL4C ubiquitination. Functionally, ARL4C enhanced the progression of GBM cells in vitro and in vivo. Moreover, microarray profiling and GST pull-down assay identified that ARL4C accelerated tumor progression via RAC1-mediated filopodium formation. Importantly, targeting PTEN potently inhibited GBM tumor progression in vitro and in vivo, whereas overexpression of ARL4C reversed the tumor progression impaired by PTEN overexpression. Clinically, analyses with patients' specimens validated a negative correlation between PTEN and ARL4C expression. Elevated ARL4C expression but PTEN deficiency in tumor was associated with poorer disease-free survival and overall survival of GBM patients. Taken together, ARL4C is critical for PTEN-deficient GBM progression and acts as a novel prognostic biomarker and a potential therapeutic candidate. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Authors: Qian Chen, Hai-Yan Weng, Xiao-Peng Tang, Yong Lin, Ye Yuan, Qian Li, Zhuo Tang, Hai-Bo Wu, Shuai Yang, Yong Li, Xi-Long Zhao, Wen-Juan Fu, Qin Niu, Hua Feng, Xia Zhang, Yan Wang, Xiu-Wu Bian, Xiao-Hong Yao
• Journal: The Journal of pathology (J Pathol) Vol. 247 Issue 2 Pg. 266-278 (02 2019) ISSN: 1096-9896 [Electronic] England
• PMID: 30357833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• RAC1 protein, human
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• ADP-Ribosylation Factors
• ARL4C protein, human
• rac1 GTP-Binding Protein

Topics

• ADP-Ribosylation Factors (genetics, metabolism)
• Animals
• Brain Neoplasms (enzymology, genetics, pathology, therapy)
• Cell Movement
• Cell Proliferation
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Glioblastoma (enzymology, genetics, pathology)
• Humans
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Invasiveness
• PTEN Phosphohydrolase (deficiency, genetics)
• Protein Stability
• Proto-Oncogene Proteins c-akt (metabolism)
• Pseudopodia (enzymology, genetics, pathology)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Tumor Cells, Cultured
• Ubiquitination
• rac1 GTP-Binding Protein (genetics, metabolism)