PMID- 30442335
OWN - NLM
STAT- MEDLINE
DCOM- 20190610
LR  - 20211204
IS  - 1879-3592 (Electronic)
IS  - 1383-5718 (Linking)
VI  - 836
IP  - Pt B
DP  - 2018 Dec
TI  - Effects of rapamycin on the mechanistic target of rapamycin (mTOR) pathway and 
      telomerase in breast cancer cells.
PG  - 103-113
LID - S1383-5718(17)30181-X [pii]
LID - 10.1016/j.mrgentox.2018.03.008 [doi]
AB  - The mTOR pathway and the enzyme telomerase are two key players commonly 
      upregulated in cancers. They render survival and proliferative advantage to 
      cancer cells, and are regarded as attractive anticancer targets. Rapamycin, a 
      macrolide antibiotic and mTOR inhibitor, has recently also been implicated in 
      telomerase inhibition and telomere attrition, although the mechanisms remain 
      poorly understood. Using breast cancer cells (MCF-7 and MDA-MB-231) wherein 
      telomerase activity and mTOR pathway are concurrently overexpressed, this study 
      sought to unravel novel mechanisms by which rapamycin may affect these pathways. 
      Short term treatment with an acute dose of rapamycin inhibited the mTOR pathway 
      and telomerase activity and induced G1 arrest. This arrest was independent of 
      cyclin D1 and p21 levels and was not mediated by DNA damage in both cell types. 
      While long term treatment with a clinically relevant dose of rapamycin resulted 
      in compromised population doubling capacity and mTOR pathway inhibition, there 
      was no effect on telomere functionality and telomerase activity as evidenced by 
      our assessments of hTERT protein levels, in vitro telomerase activity, telomere 
      length and telomere FISH analyses. We also found that sustained rapamycin 
      treatment leading to Akt activation may play a role in resistance in the more 
      invasive MDA-MB-231 cells. In summary, rapamycin specifically inhibits the 
      activation of mTOR pathway. Moreover, we show for the first time that while acute 
      short-term treatment with rapamycin induces telomerase inhibition, it does not 
      affect telomerase activity nor does it inflict telomere dysfunction in breast 
      cancer cells upon chronic long-term treatment with a clinically relevant dose. 
      These findings may be useful while designing combinatorial treatment strategies 
      with rapamycin inhibition in the clinic.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Gopalakrishnan, Kalpana
AU  - Gopalakrishnan K
AD  - Department of Physiology, Yong Loo Lin School of Medicine, National University of 
      Singapore, 117593, Singapore.
FAU - Venkatesan, Shriram
AU  - Venkatesan S
AD  - Department of Physiology, Yong Loo Lin School of Medicine, National University of 
      Singapore, 117593, Singapore.
FAU - Low, Esther Su Hui
AU  - Low ESH
AD  - Department of Physiology, Yong Loo Lin School of Medicine, National University of 
      Singapore, 117593, Singapore.
FAU - Hande, M Prakash
AU  - Hande MP
AD  - Department of Physiology, Yong Loo Lin School of Medicine, National University of 
      Singapore, 117593, Singapore; Tembusu College, National University of Singapore, 
      138597, Singapore; VIT University, Vellore, 632 014, India; Mangalore University, 
      Mangalore, 574 199, India. Electronic address: phsmph@nus.edu.sg.
LA  - eng
PT  - Journal Article
DEP - 20180328
PL  - Netherlands
TA  - Mutat Res Genet Toxicol Environ Mutagen
JT  - Mutation research. Genetic toxicology and environmental mutagenesis
JID - 101632149
RN  - 0 (Antibiotics, Antineoplastic)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.7.49 (TERT protein, human)
RN  - EC 2.7.7.49 (Telomerase)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Breast Neoplasms/drug therapy/*metabolism
MH  - Cell Cycle
MH  - DNA Damage
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Telomerase/*antagonists & inhibitors
MH  - Telomere Homeostasis
MH  - Tumor Cells, Cultured
OTO - NOTNLM
OT  - Breast cancer cells
OT  - Experimental cancer therapy
OT  - Rapamycin
OT  - Telomerase
OT  - Telomeres
OT  - mTOR pathway
EDAT- 2018/11/18 06:00
MHDA- 2019/06/14 06:00
CRDT- 2018/11/17 06:00
PHST- 2017/06/15 00:00 [received]
PHST- 2018/03/09 00:00 [revised]
PHST- 2018/03/27 00:00 [accepted]
PHST- 2018/11/17 06:00 [entrez]
PHST- 2018/11/18 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
AID - S1383-5718(17)30181-X [pii]
AID - 10.1016/j.mrgentox.2018.03.008 [doi]
PST - ppublish
SO  - Mutat Res Genet Toxicol Environ Mutagen. 2018 Dec;836(Pt B):103-113. doi: 
      10.1016/j.mrgentox.2018.03.008. Epub 2018 Mar 28.