All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype

Camilla Pellegrini, Marta Columbaro, Cristina Capanni, Maria Rosaria D'Apice, Carola Cavallo, Michela Murdocca, Giovanna Lattanzi, Stefano Squarzoni

Research output: Contribution to journalArticle

Abstract

Hutchinson Gilford progeria syndrome is a fatal disorder characterized by accelerated aging, bone resorption and atherosclerosis, caused by a LMNA mutation which produces progerin, a mutant lamin A precursor. Progeria cells display progerin and prelamin A nuclear accumulation, altered histone methylation pattern, heterochromatin loss, increased DNA damage and cell cycle alterations. Since the LMNA promoter contains a retinoic acid responsive element, we investigated if all-trans retinoic acid administration could lower progerin levels in cultured fibroblasts. We also evaluated the effect of associating rapamycin, which induces autophagic degradation of progerin and prelamin A. We demonstrate that all-trans retinoic acid acts synergistically with low-dosage rapamycin reducing progerin and prelamin A, via transcriptional downregulation associated with protein degradation, and increasing the lamin A to progerin ratio. These effects rescue cell dynamics and cellular proliferation through recovery of DNA damage response factor PARP1 and chromatin-associated nuclear envelope proteins LAP2a and BAF. The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible, represents a promising new approach in Hutchinson-Gilford Progeria therapy and deserves investigation in ageing-associated disorders.

Original languageEnglish
Pages (from-to)29914-29928
Number of pages15
JournalOncotarget
Volume6
Issue number30
DOIs
Publication statusPublished - 2015

Keywords

  • All-trans retinoic acid
  • DNA damage and repair
  • Hutchinson gilford progeria syndrome
  • Premature aging
  • Rapamycin

ASJC Scopus subject areas

  • Oncology

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