The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1
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Published version
Author(s)
Type
Journal Article
Abstract
The senescence-associated secretory phenotyp
e (SASP) can be provoked by side effects of therapeutic agents, fueling
advanced complications including cancer
resistance. However, the intracellular
signal network supporting initiation and development of the SASP driven by treat
ment-induced damage remains unclear.
Here we report that the transcription fa
ctor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the
persistent SASP signaling.
As TAK1 is implicated
in dual feedforward mechanisms to
orchestrate the SASP development,
pharmacologically targeting TAK1 depri
ves cancer cells of r
esistance acquired
from treatment-damag
ed stromal cells
in vitro
and substantially promotes tumour
regression
in vivo
. Together, our study reveals a novel network that links
functionally critical molecules associ
ated with the SASP development in
therapeutic settings, thus opening new ave
nues to improve clinical outcomes and
advance precision medicine.
e (SASP) can be provoked by side effects of therapeutic agents, fueling
advanced complications including cancer
resistance. However, the intracellular
signal network supporting initiation and development of the SASP driven by treat
ment-induced damage remains unclear.
Here we report that the transcription fa
ctor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the
persistent SASP signaling.
As TAK1 is implicated
in dual feedforward mechanisms to
orchestrate the SASP development,
pharmacologically targeting TAK1 depri
ves cancer cells of r
esistance acquired
from treatment-damag
ed stromal cells
in vitro
and substantially promotes tumour
regression
in vivo
. Together, our study reveals a novel network that links
functionally critical molecules associ
ated with the SASP development in
therapeutic settings, thus opening new ave
nues to improve clinical outcomes and
advance precision medicine.
Date Issued
2018-04-30
Date Acceptance
2018-03-28
Citation
Nature Communications, 2018, 30
ISSN
2041-1723
Publisher
Nature Publishing Group
Journal / Book Title
Nature Communications
Volume
30
Copyright Statement
© The Author(s) 2018. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article
’
s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article
’
s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit
http://creativecommons.org/
licenses/by/4.0/
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article
’
s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article
’
s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit
http://creativecommons.org/
licenses/by/4.0/
Sponsor
Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Breast Cancer Now
Medical Research Council (MRC)
Grant Number
C37/A12011
2012NovemberPhD016
2012MayPR070
2014NovPhD326
MR/N012097/1
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
INFLAMMATORY CYTOKINE SECRETION
CANCER-THERAPY RESISTANCE
EPITHELIAL-CELL LINE
TUMOR MICROENVIRONMENT
PARACRINE SENESCENCE
DAMAGE
NETWORK
CHEMOSENSITIVITY
TUMORIGENESIS
CHEMOTHERAPY
MD Multidisciplinary
Publication Status
Published
Article Number
ARTN 1723