title: Renal tumours in a Tsc2(+/-) mouse model do not show feedback inhibition of Akt and are effectively prevented by rapamycin.
abstract: Tuberous sclerosis (TSC) is an inherited syndrome in which tumours in multiple organs are characterised by activation of mammalian target of rapamycin complex 1 (mTORC1). Previous work suggests that mTORC1 activation is associated with feedback inhibition of Akt, a substrate of mTORC2. This could limit TSC-associated tumour growth but lead to paradoxical promotion of tumour cell survival upon treatment with mTOR inhibitors. However, Akt/mTOR signalling has not been fully investigated in TSC-associated tumours and it has been uncertain whether mTOR inhibition can prevent TSC-associated renal tumourigenesis. In this study, we investigated Akt/mTOR signalling in renal tumours using a Tsc2(+/-) mouse model and tested whether mTOR inhibition could prevent renal tumourigenesis. We found that all renal lesions including cysts, adenomas and carcinomas exhibited activation of both Akt and mTORC1 as evidenced by increased protein expression and phosphorylation of Akt and mTOR and their downstream targets. Protein kinase Cα was also highly expressed and phosphorylated in these lesions, consistent with activation of mTORC2. Surprisingly, IRS proteins were highly expressed, in contrast to a striking decrease seen in cultured Tsc2(-/-) mouse embryonic fibroblasts, suggesting one mechanism through which loss of feedback inhibition of Akt may occur in mTORC1 hyperactivated Tsc-associated tumours. Long-term treatment with rapamycin reduced both Akt and mTORC1 activity in normal kidney tissues and blocked the development of all types of renal lesions. In conclusion, in contrast to previous studies, we found that Akt signalling is not inhibited in Tsc-associated renal lesions and that by partially inhibiting the Akt/mTOR pathway, rapamycin is highly effective in preventing Tsc-associated tumours.
authors.affiliation: Institute of Medical Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Institute of Medical Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: M
authors.initials: M
authors.lastname: Kalogerou
authors.affiliation: Institute of Medical Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Samsel
authors.affiliation: Institute of Medical Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Section of Pathology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: D F R
authors.initials: DF
authors.lastname: Griffiths
authors.affiliation: Department of Primary Care and Public Health, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: J
authors.initials: J
authors.lastname: Gallacher
authors.affiliation: Institute of Medical Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Sampson
authors.affiliation: Institute of Medical Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Shen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D046912:Multiprotein Complexes; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus