GABARAPL1 suppresses metastasis by counteracting PI3K/Akt pathway in prostate cancer
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Wei Su1,*, Shibao Li2,*, Xiaofan Chen3, Lingyu Yin2, Ping Ma2, Yingyu Ma4, Bing Su5,6
1Department of Orthopedics, The Third Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China
2Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China
3Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, Guangdong, China
4Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
5Xinxiang Key Lab of Translational Cancer Research, The Third Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China
6Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA
*These authors contributed equally to this work
Yingyu Ma, email: [email protected]
Bing Su, email: [email protected]
Keywords: GABARAPL1, prostate cancer, metastasis, Akt, FOXOs
Received: August 15, 2016 Accepted: December 02, 2016 Published: December 10, 2016
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.
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