Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A

Abstract

// Bi-Hong Xu 1,* , Xiao-Xing Li 1,* , Yang Yang 1 , Mei-Yin Zhang 1 , Hui-Lan Rao 2 , Hui-Yun Wang 1,3 and X.F. Steven Zheng 1,3 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China 2 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China 3 Rutgers Cancer Institute of New Jersey and Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA * These authors have contributed equally to this work Correspondence to: X.F. Steven Zheng, email: // Hui-Yun Wang, email: // Keywords : signal transduction, Rab1A, mTORC1, cancer, rapamycin Received : June 20, 2015 Accepted : July 28, 2015 Published : August 13, 2015 Abstract mTORC1 is a master regulator of cell growth and proliferation, and an established anticancer drug target. Aberrant mTORC1 signaling is common in hepatocellular carcinoma (HCC), but the underlying mechanism remains elusive. Rab1A is a newly identified mTORC1 activator that mediates an alternative amino acid (AA) signaling branch to Rag GTPases. Because liver is a physiological hub for nutrient sensing and metabolic homeostasis, we investigated the possible role of Rab1A in HCC. We found that Rab1A is frequently overexpressed in HCC, which enhances hyperactive AA-mTORC1 signaling, promoting malignant growth and metastasis of HCC in vitro and in vivo . Moreover, aberrant Rab1A expression is closely associated with poor prognosis. Strikingly, aberrant Rab1A overexpression leads to increased rapamycin sensitivity, indicating that inappropriate activation of AA signaling is a cancer-driving event in HCC. Our findings further suggest that Rab1A is a valuable biomarker for prognosis and personalized mTORC1-targeted therapy in liver cancer.