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

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.

Structure of prodigiosin from Serratia marcescens NJZT-1 and its cytotoxicity on TSC2-null cells

“…The red pigment extracted from strain NJZT-1 were next determined by the high performance liquid chromatography coupled with mass spectrometry (HPLC-MS). Our results from the HPLC analysis showed that, the major product was eluted at 14.323 min ( Figure 4A), similar to the pervious investigation of prodigiosin (Li et al, 2016). Moreover, as shown in Figure 4B, there was a molecular ion peak M + H of prodigiosin at m/z 324, which corresponded to the molecular weight of prodigiosin (C 20 H 25 N 3 O, 323 kD).…”

A survey of transcriptome complexity in Sus scrofa using single-molecule long-read sequencing

“…MT-CO2 is usually unexpressed and has the characteristic of inducible expression. Once the transcript originates from MT-CO2 expression, it can induce tumour occurrence 50 and increase the probability of inducing tumour in females. 51 Moreover, fusion event could not only span two distinct genes but also produce variant isoforms with AS events.…”

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

“…Cell proliferation was measured by an MTT assay according to the manufacturer's instructions and has been described previously [ 29 ]. For the cell viability assays, Tsc1- or Tsc2-null MEFs were seeded in 96-well plates at a density of 3, 000 cells/well and treated with DMSO, rapamycin, AG1295, or combination of rapamycin and AG1295 for 48 h. Followed by added 10 μl of Cell Counting Kit-8 reagent (Beyotime, China) to per well and incubated the plates for 1 h, the optical density (OD value) of each well was measured at 450 nm.…”