Clonal cell populations unresponsive to radiosensitization induced
by telomerase inhibition
, Hyun-Jin Shin
, Jeong-Eun Park
, Kyoung-Mi Juhn
, Seon Rang Woo
, Hee-Young Kim
, Sang-Gu Hwang
, Sung-Hee Hong
, Chang-Mo Kang
, Young-Do Yoo
, Myung-Haing Cho
, Gil Hong Park
, Kee-Ho Lee
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea
Laboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Republic of Korea
Division of Natural Science, Seoul Women’s University, Seoul 139-774, Republic of Korea
Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
Department of Biochemistry, College of Medicine, Korea University, Seoul, Republic of Korea
Received 20 September 2010
Available online 27 September 2010
Chromosomal end-to-end fusion
A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are
to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telo-
mere shortening. After extensive division of individual transformed clones of mTERC
cells, about 22%
of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telo-
mere lengths of unsensitized mTERC
clones were reduced, as were those of most sensitized clones.
However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted
in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when
telomeres become shorter under conditions of telomerase deﬁciency, and results in unresponsiveness to
the radiosensitization generally mediated by telomere shortening.
Ó 2010 Elsevier Inc. All rights reserved.
A shortcoming of current radiotherapy procedures is frequent
relapse, with emergence of radioresistant remnant cells, after elim-
ination of a large proportion of tumor cells. This issue is both fun-
damental and unresolved, and has encouraged the development of
targeted molecular therapy seeking to sensitize tumor cells to radi-
ation. In practice, many potential targets have been identiﬁed, and
modulators thereof may enhance the radiosensitivity of radioresis-
tant human tumors [1,2]. Telomere length and telomerase inhibi-
tion activity are viewed as useful predictors of radiosensitivity
and radiosensitizer status, respectively. Such evaluation was ini-
tially encouraged by the fact that a particular telomerase enzyme,
defective in normal somatic cells, is active in most human tumor
cells, in over 80% of tumor cell types [3,4].
This distinct difference in molecular background between
tumor and normal cells has encouraged the inception of diverse
studies exploring connections between radiosensitivity and
telomere length or telomerase activity. Accelerated telomere short-
ening is common in radiosensitive cells derived from patients with
conditions such as ataxia-telangiectasia, Nijmegen breakage, and
Fanconi anemia syndrome . Human ﬁbroblasts with long telo-
meres were signiﬁcantly more radio-resistant than were otherwise
equivalent ﬁbroblasts in which telomeres became shorter upon re-
peated passage . This inverse relationship between telomere
length and radiation sensitivity has been veriﬁed in mouse  and
human cancer cells [8,9]. In a mouse model system deﬁcient in tel-
omerase, organs and cells formed late in telomerase-deﬁcient ani-
mals (thus with shortened telomeres) were more radiosensitive
than were tissues/cells from mice with longer telomeres .
The fact that telomere length is inversely correlated with radio-
sensitivity has potential clinical applications. Telomere length in
tumor cells of individual patients may be useful in predicting the
response to radiotherapy , and radioresistant tumor cells
expressing telomerase may be sensitized by shortening of telo-
meres mediated by telomerase inhibition. A strategy based on radi-
osensitization by telomerase inhibition is attractive because
human cancer cells have shorter telomeres than do matched
somatic and peripheral blood cells .
0006-291X/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
Abbreviations: PDL, population doubling level; TRF, telomeric restriction
Corresponding authors. Address: Department of Radiation Cancer Research,
Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong,
Nowon-Ku, Seoul 139-706, Republic of Korea (K.-H. Lee).
E-mail addresses: email@example.com (G.H. Park), firstname.lastname@example.org (K.-H.
These two authors contributed equally to this work.
Biochemical and Biophysical Research Communications 402 (2010) 198–202
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