Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

// Li Wang 1, * , Zhaofei Ni 1, * , Yujie Liu 2, * , Shuang Ji 1 , Fuquan Jin 1 , Keguo Jiang 3 , Junfang Ma 4 , Cuiping Ren 5 , Hongbing Zhang 6 , Zhongdong Hu 7 and Xiaojun Zha 1 1 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China 2 The First Clinical Medical School, Anhui Medical University, Hefei, China 3 Department of Nephrology, The Third Affiliated Hospital of Anhui Medical University, Hefei, China 4 Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 5 Department of Parasitology, School of Basic Medicine, Anhui Medical University, Hefei, China 6 State Key Laboratory of Medical Molecular Biology, Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 7 Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China * These authors contributed equally to this work Correspondence to: Xiaojun Zha, email: zhaxiaojunpumc@gmail.com Zhongdong Hu, email: zdhu@bucm.edu.cn Keywords: mTOR, FOXO3a, PDGFRα, AKT, tumorigenesis Received: January 30, 2017      Accepted: June 18, 2017      Published: July 04, 2017 ABSTRACT Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss-of-function mutations in either the TSC1 or TSC2 gene, leads to the development of tuberous sclerosis complex (TSC), a benign tumor syndrome with multiple affected organs. mTORC1-mediated inhibition of AKT constrains the tumor progression of TSC, but the exact mechanisms remain unclear. Herein we showed that loss of TSC1 or TSC2 downregulation of platelet-derived growth factor receptor α (PDGFRα) expression was mediated by mTORC1. Moreover, mTORC1 inhibited PDGFRα expression via suppression of forkhead box O3a (FOXO3a)-mediated PDGFRα gene transcription. In addition, ectopic expression of PDGFRα promoted AKT activation and enhanced proliferation and tumorigenic capacity of Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs), and vice versa. Most importantly, rapamycin in combination with AG1295, a PDGFR inhibitor, significantly inhibited growth of TSC1/TSC2 complex-deficient cells in vitro and in vivo . Therefore, downregulated FOXO3a/PDGFRα/AKT pathway exerts a protective effect against hyperactivated mTORC1-induced tumorigenesis caused by loss of TSC1/TSC2 complex, and the combination of rapamycin and AG1295 may be a new effective strategy for TSC-associated tumors treatment.