title: Renal tumours in a Tsc1+/- mouse model show epigenetic suppression of organic cation transporters Slc22a1, Slc22a2 and Slc22a3, and do not respond to metformin.
abstract: Metformin, a substrate of several poly-specific organic cation transporters, is a widely used biguanide for the treatment of type II diabetes. Recent studies suggest that metformin attenuates mTORC1 signalling by the activation of 5' adenosine monophosphate-activated protein kinase (AMPK) in the presence or absence of a functional hamartin/tuberin (TSC1/TSC2) complex. Metformin has also been reported to inhibit mTORC1 independent of AMPK through p53-dependent regulated in development and DNA damage responses 1 (REDD1) or by inhibiting Rag GTPases. These observations suggest that metformin could have therapeutic potential for tuberous sclerosis, an inherited disorder characterised by the aberrant activation of mTORC1 and the development of tumours in many organs, including the kidneys. In this study, we investigated the effect of metformin on renal lesions in a Tsc1(+/-) mouse model of tuberous sclerosis. Continuous treatment of metformin for 9 months at doses of up to 600 mg/kg/day had no significant effect on renal lesions in nine treated mice compared to 10 controls. Metformin treatment appeared to attenuate mTORC1 signalling in Tsc1(+/-) kidney tissues but not in renal tumours. Surprisingly, the expression of the organic cation transporters Slc22a1, Slc22a2 and Slc22a3 essential for the cellular uptake of metformin was highly suppressed in renal tumours. Treatment of cultured cells derived from a Tsc1-associated renal tumour with 5-aza-2-deoxycytidine or trichostatin A greatly increased the expression of these genes. These data suggest that the epigenetic suppression of the organic cation transporters in Tsc-associated mouse renal tumours may contribute to the lack of response to metformin treatment.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Maria
authors.initials: M
authors.lastname: Kalogerou
authors.forename: John
authors.initials: J
authors.lastname: Gallacher
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.forename: Ming Hong
authors.initials: MH
authors.lastname: Shen
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000077209:Decitabine; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*; D000099254:Organic Cation Transporter 3
chemical_list: D001374:Azacitidine; D050482:Catecholamine Plasma Membrane Transport Proteins; D000077209:Decitabine; D006655:Histone Deacetylases; D007004:Hypoglycemic Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin; D046912:Multiprotein Complexes; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000099254:Organic Cation Transporter 3; C103766:Slc22a1 protein, mouse; C491012:Slc22a2 protein, mouse; C000624651:Tsc1 protein, mouse