Oncotarget

Research Papers:

mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency

Hongwu Li _, Fuquan Jin, Keguo Jiang, Shuang Ji, Li Wang, Zhaofei Ni, Xianguo Chen, Zhongdong Hu, Hongbing Zhang, Yehai Liu, Yide Qin and Xiaojun Zha

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Oncotarget. 2016; 7:28435-28447. https://doi.org/10.18632/oncotarget.8633

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Abstract

Hongwu Li1,3,*, Fuquan Jin2,4,*, Keguo Jiang2,5,*, Shuang Ji2, Li Wang2, Zhaofei Ni2, Xianguo Chen6, Zhongdong Hu7, Hongbing Zhang8, Yehai Liu1, Yide Qin2, Xiaojun Zha2,9

1Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China

2Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China

3Department of Otorhinolaryngology, Head & Neck Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China

4School of Pharmacy, Anhui Medical University, Hefei, China

5Department of Nephrology, The Third Affiliated Hospital of Anhui Medical University, Hefei, China

6Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

7Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

8State Key Laboratory of Medical Molecular Biology, Department of Physiology & Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

9State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, China

*These authors have contributed equally to this work

Correspondence to:

Yehai Liu, email: [email protected]

Yide Qin, email: [email protected]

Xiaojun Zha, email: [email protected]

Keywords: mTOR, STAT3, COX2, TSC, IL-6

Received: January 16, 2016     Accepted: March 28, 2016     Published: April 7, 2016

ABSTRACT

Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in the TSC1 or TSC2 gene, is characterized by benign tumor formation in multiple organs. Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) is the primary alteration underlying TSC tumors. By analyzing Tsc2-null mouse embryonic fibroblasts (MEFs) and rat uterine leiomyoma-derived Tsc2-null ELT3 cells, we detected evidence for the involvement of cyclooxygenase 2 (COX2) as a downstream target of mTORC1 in the development of TSC tumors. We showed that loss of TSC2 led to decreased COX2 expression through activation of an mTORC1/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Overexpression of COX2 promoted proliferation and tumoral growth of Tsc2-null cells. COX2 knockdown inhibited the proliferation of the control cells. COX2 enhanced Tsc2-null cell growth through upregulation of interleukin-6 (IL-6). In addition, rapamycin in combination with celecoxib, a COX2 inhibitor, strongly inhibited Tsc2-deficient cell growth. We conclude that downregulation of COX2 exerts a protective effect against hyperactivated mTORC1-mediated tumorigenesis caused by the loss of TSC2, and the combination of rapamycin and celecoxib may be an effective new approach to treating TSC.


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