Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer

Cell. 2012 Feb 17;148(4):651-63. doi: 10.1016/j.cell.2011.12.028.

Abstract

To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm(-/-) mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Gene Knockdown Techniques
  • Genes, cdc
  • Humans
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / metabolism
  • Lymphoma, T-Cell / pathology
  • Mice
  • Mitochondria* / metabolism
  • Neoplasm Invasiveness / pathology
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Reactive Oxygen Species / metabolism
  • Receptors, Estrogen / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Telomerase / antagonists & inhibitors*
  • Telomerase / genetics
  • Telomerase / metabolism
  • Telomere Homeostasis*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Reactive Oxygen Species
  • Receptors, Estrogen
  • Transcription Factors
  • Tumor Suppressor Proteins
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Superoxide Dismutase
  • superoxide dismutase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • Telomerase

Associated data

  • GEO/GSE35044
  • GEO/GSE35045