In situ analysis of mTORC1/2 and cellular metabolism–related proteins in human Lymphangioleiomyomatosis

Ildiko Krencz, Anna Sebestyen, Judit Papay, Andras Jeney, Zoltan Hujber, Charles Dwayne Burger, Cesar A. Keller, Andras Khoor

Research output: Contribution to journalArticle

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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 (P <.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.

Original languageEnglish (US)
Pages (from-to)199-207
Number of pages9
JournalHuman Pathology
Volume79
DOIs
StatePublished - Sep 1 2018

Fingerprint

Lymphangioleiomyomatosis
Proteins
Metabolic Networks and Pathways
Smooth Muscle Myocytes
S 6
Energy Metabolism
TOR Serine-Threonine Kinases
Sirolimus
Disease Progression
Acetates
Fatty Acids
Therapeutics

Keywords

  • Cellular metabolism
  • Immunohistochemistry
  • Lymphangioleiomyomatosis
  • mTORC1
  • mTORC2

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

In situ analysis of mTORC1/2 and cellular metabolism–related proteins in human Lymphangioleiomyomatosis. / Krencz, Ildiko; Sebestyen, Anna; Papay, Judit; Jeney, Andras; Hujber, Zoltan; Burger, Charles Dwayne; Keller, Cesar A.; Khoor, Andras.

In: Human Pathology, Vol. 79, 01.09.2018, p. 199-207.

Research output: Contribution to journalArticle

Krencz, Ildiko ; Sebestyen, Anna ; Papay, Judit ; Jeney, Andras ; Hujber, Zoltan ; Burger, Charles Dwayne ; Keller, Cesar A. ; Khoor, Andras. / In situ analysis of mTORC1/2 and cellular metabolism–related proteins in human Lymphangioleiomyomatosis. In: Human Pathology. 2018 ; Vol. 79. pp. 199-207.
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AU - Krencz, Ildiko

AU - Sebestyen, Anna

AU - Papay, Judit

AU - Jeney, Andras

AU - Hujber, Zoltan

AU - Burger, Charles Dwayne

AU - Keller, Cesar A.

AU - Khoor, Andras

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AB - 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 (P <.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.

KW - Cellular metabolism

KW - Immunohistochemistry

KW - Lymphangioleiomyomatosis

KW - mTORC1

KW - mTORC2

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