MnTE-2-PyP Treatment, or NOX4 Inhibition, Protects against Radiation-Induced
Damage in Mouse Primary Prostate Fibroblasts by Inhibiting the TGF-Beta 1
Signaling Pathway
#MMPMID28225655
Chatterjee A
; Kosmacek EA
; Oberley-Deegan RE
Radiat Res
2017[Mar]; 187
(3
): 367-381
PMID28225655
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Prostate cancer patients who undergo radiotherapy frequently suffer from side
effects caused by radiation-induced damage to normal tissues adjacent to the
tumor. Exposure of these normal cells during radiation treatment can result in
tissue fibrosis and cellular senescence, which ultimately leads to
postirradiation-related chronic complications including urinary urgency and
frequency, erectile dysfunction, urethral stricture and incontinence.
Radiation-induced reactive oxygen species (ROS) have been reported as the most
potent causative factor for radiation damage to normal tissue. While MnTE-2-PyP,
a ROS scavenger, protects normal cells from radiation-induced damage, it does not
protect cancer cells during radiation treatment. However, the mechanism by which
MnTE-2-PyP provides protection from radiation-induced fibrosis has been unclear.
Our current study reveals the underlying molecular mechanism of radiation
protection by MnTE-2-PyP in normal mouse prostate fibroblast cells. To
investigate the role of MnTE-2-PyP in normal tissue protection after irradiation,
primary prostate fibroblasts from C57BL/6 mice were cultured in the presence or
absence of MnTE-2-PyP and exposed to 2 Gy of X rays. We found that MnTE-2-PyP
could protect primary prostate fibroblasts from radiation-induced activation, as
measured by the contraction of collagen discs, and senescence, detected by
beta-galactosidase staining. We observed that MnTE-2-PyP inhibited the
TGF-?-mediated fibroblast activation pathway by downregulating the expression of
TGF-? receptor 2, which in turn reduced the activation and/or expression of
SMAD2, SMAD3 and SMAD4. As a result, SMAD2/3-mediated transcription of
profibrotic markers was reduced by MnTE-2-PyP. Due to the inhibition of the TGF-?
pathway, fibroblasts treated with MnTE-2-PyP could resist radiation-induced
activation and senescence. NADPH oxidase 4 (NOX4) expression is upregulated after
irradiation and produces ROS. As was observed with MnTE-2-PyP treatment,
NOX4(-/-) fibroblasts were protected from radiation-induced fibroblast activation
and senescence. However, NOX4(-/-) fibroblasts had reduced levels of active
TGF-?1, which resulted in decreased TGF-? signaling. Therefore, our data suggest
that reduction of ROS levels, either by MnTE-2-PyP treatment or by eliminating
NOX4 activity, significantly protects normal prostate tissues from
radiation-induced tissue damage, but that these approaches work on different
components of the TGF-? signaling pathway. This study proposes a crucial insight
into the molecular mechanism executed by MnTE-2-PyP when utilized as a
radioprotector. An understanding of how this molecule works as a radioprotector
will lead to a better controlled mode of treatment for post therapy complications
in prostate cancer patients.
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