Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer.

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.

journal_name

Cell

journal_title

Cell

authors

Hu J,Hwang SS,Liesa M,Gan B,Sahin E,Jaskelioff M,Ding Z,Ying H,Boutin AT,Zhang H,Johnson S,Ivanova E,Kost-Alimova M,Protopopov A,Wang YA,Shirihai OS,Chin L,DePinho RA

doi

10.1016/j.cell.2011.12.028

subject

Has Abstract

pub_date

2012-02-17 00:00:00

pages

651-63

issue

4

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(12)00026-8

journal_volume

148

pub_type

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