Oncotarget

Research Papers:

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

Li Wang, Zhaofei Ni, Yujie Liu, Shuang Ji, Fuquan Jin, Keguo Jiang, Junfang Ma, Cuiping Ren, Hongbing Zhang, Zhongdong Hu and Xiaojun Zha _

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Oncotarget. 2017; 8:54858-54872. https://doi.org/10.18632/oncotarget.18963

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Abstract

Li Wang1,*, Zhaofei Ni1,*, Yujie Liu2,*, Shuang Ji1, Fuquan Jin1, Keguo Jiang3, Junfang Ma4, Cuiping Ren5, Hongbing Zhang6, Zhongdong Hu7 and Xiaojun Zha1

1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China

2The First Clinical Medical School, Anhui Medical University, Hefei, China

3Department of Nephrology, The Third Affiliated Hospital of Anhui Medical University, Hefei, China

4Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China

5Department of Parasitology, School of Basic Medicine, Anhui Medical University, Hefei, China

6State 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

7Modern 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: [email protected]

Zhongdong Hu, email: [email protected]

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.


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