Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair

Acta Pharmacologica Sinica
Xiao-Qin LiJian Li

Abstract

For the majority of patients with advanced non-small cell lung cancer (NSCLC), the standard of care remains platinum-based chemotherapy. However, cisplatin resistance is a big obstacle to the treatment, and elucidation of its mechanism is warranted. In this study, we showed that there was no difference in intracellular uptake of cisplatin or the removal of platinum-DNA adducts between a cisplatin-resistant NSCLC cell line (A549/DR) and a cisplatin-sensitive NSCLC cell line (A549). However, the capacity to repair DNA interstrand crosslinks (ICLs) and double-strand breaks (DSBs) was significantly enhanced in the A549/DR cell line compared to 3 cisplatin-sensitive cell lines. We found that the protein and mRNA expression levels of Pol η, a Y-family translesion synthesis (TLS) polymerase, were markedly increased upon cisplatin exposure in A549/DR cells compared with A549 cells. Furthermore, intracellular co-localization of Pol η and proliferation cell nuclear antigen (PCNA) induced by cisplatin or cisplatin plus gemcitabine treatment was inhibited by depleting ataxia telangiectasia mutated and Rad-3-related (ATR). Pol η depletion by siRNA sensitized A549/DR cells to cisplatin; co-depletion of Pol η and ATR further increased A549/DR...Continue Reading

References

Feb 13, 2003·Biochemistry·Jody M HavenerStephen G Chaney
Aug 18, 2004·Genes & Development·Paul R AndreassenToshiyasu Taniguchi
Sep 18, 2004·Cancer Research·Ekaterina BassettMarila Cordeiro-Stone
Dec 21, 2004·Critical Reviews in Oncology/hematology·Stephen G ChaneyYibing Wu
Nov 4, 2005·Cancer Research·Mark R AlbertellaMark J O'Connor
Apr 11, 2006·Molecular Cancer Research : MCR·Yih-wen ChenKai-ming Chou
Jan 30, 2008·Nature Reviews. Genetics·Andrés Aguilera, Belén Gómez-González
Mar 5, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lainie P MartinRussell J Schilder
Apr 15, 2008·Trends in Biochemical Sciences·Suse BroydeDinshaw J Patel
Jul 3, 2008·Nature Reviews. Molecular Cell Biology·Karlene A Cimprich, David Cortez
Oct 11, 2008·Proceedings of the National Academy of Sciences of the United States of America·Atsuko NiimiAlan R Lehmann
Oct 24, 2008·Proceedings of the National Academy of Sciences of the United States of America·Yih-Wen ChenKai-Ming Chou
Feb 4, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Paolo CeppiGiorgio Scagliotti
Feb 4, 2010·Human Molecular Genetics·Emmanuelle DesprasPatricia L Kannouche
Feb 24, 2010·Nature Reviews. Molecular Cell Biology·Dana Branzei, Marco Foiani
Nov 12, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jason DolesMichael T Hemann
Nov 12, 2010·Proceedings of the National Academy of Sciences of the United States of America·Kun XieGraham C Walker
Jun 15, 2011·Nucleic Acids Research·The Vinh HoOrlando D Schärer
Nov 16, 2011·International Journal of Proteomics·K C SummersL H Malkas
Jan 20, 2012·Nature·Christopher J Lord, Alan Ashworth
Feb 16, 2012·Chemical Research in Toxicology·Alex R KlugIrina G Minko
Mar 6, 2012·Molecular Pharmacology·Shilpy SharmaChristine E Canman
Apr 25, 2012·Proceedings of the National Academy of Sciences of the United States of America·Ye ZhaoWei Yang
Apr 3, 2013·Archives of Pathology & Laboratory Medicine·Kirtee RapariaMinesh P Mehta
May 24, 2013·Cancer Research·Thiyam Ramsing SinghAmom Ruhikanta Meetei
Oct 3, 2013·Cold Spring Harbor Perspectives in Biology·Cheryl ClausonLaura Niedernhofer
Nov 6, 2015·International Journal of Cancer. Journal International Du Cancer·Joan MinguetPeter Bramlage

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BETA
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transfection
PCR
transfections
flow cytometry

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ModFit LT
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