Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8807453 | Human Pathology | 2018 | 28 Pages |
Abstract
Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease with features of a low-grade neoplasm. It is primarily caused by mutations in TSC1 or TSC2 genes. Sirolimus, an inhibitor of mTOR complex 1 (mTORC1), slows down disease progression in some, but not all patients. Hitherto, other potential therapeutic targets such as mTOR complex 2 (mTORC2) and various metabolic pathways have not been investigated in human LAM tissues. The aim of this study was to assess activities of mTORC1, mTORC2 and various metabolic pathways in human LAM tissues through analysis of protein expression. Immunohistochemical analysis of p-S6 (mTORC1 downstream protein), Rictor (mTORC2 scaffold protein) as well as GLUT1, GAPDH, ATPB, GLS, MCT1, ACSS2 and CPT1A (metabolic pathway markers) were performed on lung tissue from 11 patients with sporadic LAM. Immunoreactivity was assessed in LAM cells with bronchial smooth muscle cells as controls. Expression of p-S6, Rictor, GAPDH, GLS, MCT1, ACSS2 and CPT1A was significantly higher in LAM cells than in bronchial smooth muscle cells (Pâ¯<â¯.01). No significant differences were found between LAM cells and normal bronchial smooth muscle cells in GLUT1 and ATPB expression. The results are uniquely derived from human tissue and indicate that, in addition to mTORC1, mTORC2 may also play an important role in the pathobiology of LAM. Furthermore, glutaminolysis, acetate utilization and fatty acid β-oxidation appear to be the preferred bioenergetic pathways in LAM cells. mTORC2 and these preferred bioenergetic pathways appear worthy of further study as they may represent possible therapeutic targets in the treatment of LAM.
Keywords
Acss2TSC2GAPDHmTORCpt1amTOR complex 2GLSHMB-45BSMGLUT1mTORC2Mct1atpBmTORC1mTOR complex 1smooth muscle actinImmunohistochemistrySMARictorbronchial smooth muscleLAMLymphangioleiomyomatosisCellular metabolismmonocarboxylate transporter 1mammalian target of rapamycincarnitine palmitoyltransferase 1aGlutaminaseglucose transporter 1glyceraldehyde 3-phosphate dehydrogenaseEstrogen receptor
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Authors
Ildiko MD, Anna MSc, PhD, Judit MD, PhD, Andras MD, PhD, DSc, Zoltan PharmD, Charles D. MDFCCP, Cesar A. MD, Andras MD, PhD,