title: GABARAPL1 suppresses metastasis by counteracting PI3K/Akt pathway in prostate cancer.
abstract: Metastasis remains the primary cause of prostate cancer (CaP)-related death. Using a genome wide shRNA screen, we identified GABARAPL1 as a potential CaP metastasis suppressor. GABARAPL1 mRNA levels inversely correlate with the invasive potential of a panel of human CaP cell lines. Lower mRNA levels correlate with higher Gleason scores in clinical CaP tumor samples. Moreover, Kaplan-Meier curves analysis showed that GABARAPL1 down-regulation in cancer tissues is associated with decreased disease-free survival in CaP patients. Knockdown of GABARAPL1 in human LNCaP cells results in increased invasion in vitro and lymph node metastasis in vivo. Vice versa, ectopic expression of GABARAPL1 decreases the invasiveness of CWR22Rv1 cells. Our previous in vitro shRNA screening identified FOXO4, a PI3K/Akt-inactivating downstream target, as a potential CaP metastasis suppressor. We show here that silencing FOXOs leads to reduced GABARAPL1 expression and enhanced invasion in LNCaP cells. Transfection of constitutively-activated Akt (myr-Akt) increased the invasion of LNCaP cells, which is associated with the inactivation of FOXOs and decreased GABARAPL1 expression. Indeed, forced expression of GABARAPL1 reversed the increased invasiveness of LNCaP/myr-Akt cells. Finally, immunohistochemistry analysis shows that Akt phosphorylation is negatively correlated with GABARAPL1 expression in human CaP tissues. Taken together, our data indicate that the suppression of FOXOs-GABARAPL1 signaling by Akt is an important mechanism for CaP progression and metastasis.
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Su
authors.affiliation: Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Shibao
authors.initials: S
authors.lastname: Li
authors.affiliation: Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, Guangdong, China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Xinxiang Key Lab of Translational Cancer Research, The Third Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China.|Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C430503:GABARAPL1 protein, human; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; FOXOs; GABARAPL1; metastasis; prostate cancer