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.
Highlights
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by formation of benign tumors in multiple organs, including kidney, brain, and skin [1,2,3]
We showed that loss of TSC2 led to decreased cyclooxygenase 2 (COX2) expression through activation of an mammalian target of rapamycin complex 1 (mTORC1)/signal transducer and activator of transcription 3 (STAT3) signaling pathway
The fact that COX2 is frequently deregulated in tumors and that TSC is characterized by benign tumor formation in multiple organs prompted us to investigate the role of COX2 in the development of TSC tumors
Summary
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by formation of benign tumors in multiple organs, including kidney, brain, and skin [1,2,3]. This disorder is caused by inactivating mutations in either of two tumor suppressor genes: TSC1 or TSC2 [4]. It is believed that the negative feedback inhibition of AKT by the dysregulated mTORC1 is the major reason for the benign nature of TSC tumors [9, 10], whether additional signaling molecules contribute to restrict tumor development remains less clear
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