Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer.

The Journal of Biological Chemistry
Kiran MahajanNupam P Mahajan

Abstract

Androgen deprivation therapy has been the standard of care in prostate cancer due to its effectiveness in initial stages. However, the disease recurs, and this recurrent cancer is referred to as castration-resistant prostate cancer (CRPC). Radiotherapy is the treatment of choice; however, in addition to androgen independence, CRPC is often resistant to radiotherapy, making radioresistant CRPC an incurable disease. The molecular mechanisms by which CRPC cells acquire radioresistance are unclear. Androgen receptor (AR)-tyrosine 267 phosphorylation by Ack1 tyrosine kinase (also known as TNK2) has emerged as an important mechanism of CRPC growth. Here, we demonstrate that pTyr(267)-AR is recruited to the ATM (ataxia telangiectasia mutated) enhancer in an Ack1-dependent manner to up-regulate ATM expression. Mice engineered to express activated Ack1 exhibited a significant increase in pTyr(267)-AR and ATM levels. Furthermore, primary human CRPCs with up-regulated activated Ack1 and pTyr(267)-AR also exhibited significant increase in ATM expression. The Ack1 inhibitor AIM-100 not only inhibited Ack1 activity but also was able to suppress AR Tyr(267) phosphorylation and its recruitment to the ATM enhancer. Notably, AIM-100 suppressed A...Continue Reading

References

Jan 5, 2002·Acta Oncologica·M B KastanD Yang
Jan 16, 2003·Oncogene·Eli Berkovich, Doron Ginsberg
Jan 31, 2003·Nature·Christopher J Bakkenist, Michael B Kastan
Mar 4, 2003·Nature Reviews. Cancer·Yosef Shiloh
Jul 5, 2003·The Journal of Clinical Endocrinology and Metabolism·Ivan V LitvinovJohn T Isaacs
Sep 10, 2003·Proceedings of the National Academy of Sciences of the United States of America·Kiran N Mahajan, Beverly S Mitchell
Jan 2, 2004·Nature Medicine·Charlie D ChenCharles L Sawyers
Jan 5, 2005·International Journal of Radiation Oncology, Biology, Physics·Jamie A CesarettiBarry S Rosenstein
Oct 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Edward Htun van der HorstScott Powers
Feb 17, 2007·Current Opinion in Cell Biology·Jiri Bartek, Jiri Lukas
May 15, 2007·Proceedings of the National Academy of Sciences of the United States of America·Nupam P MahajanYoung E Whang
Feb 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Adrian Salic, Timothy J Mitchison
Aug 5, 2008·Current Opinion in Pharmacology·Yu ChenHoward I Scher
May 19, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ricardo M AttarMarco M Gottardis
Jul 30, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Trevor J PughRichard A Moore
Oct 23, 2009·Nature·Stephen P Jackson, Jiri Bartek
Jan 30, 2010·The Journal of Biological Chemistry·Victoria Prieto-EchagüeW Todd Miller
Mar 25, 2010·PloS One·Kiran MahajanNupam P Mahajan
May 1, 2010·Journal of Cellular Physiology·Kiran Mahajan, Nupam P Mahajan
May 21, 2010·Drugs·Giuseppe Di LorenzoCora N Sternberg
Jun 29, 2010·Cancer Cell·Barry S TaylorWilliam L Gerald
Aug 4, 2010·Genome Integrity·Zhiming FangRaymond A Clarke
Feb 7, 2012·Journal of Cellular Physiology·Kiran Mahajan, Nupam P Mahajan
Feb 11, 2012·The American Journal of Pathology·Kiran MahajanNupam P Mahajan

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Citations

Aug 14, 2012·Nature Structural & Molecular Biology·Kiran MahajanNupam P Mahajan
Jul 16, 2013·Oncogene·C A Cremona, A Behrens
Sep 3, 2014·Breast Cancer Research and Treatment·Yassine RechoumSuzanne A W Fuqua
Jan 16, 2014·Endocrine-related Cancer·Yulia KoryakinaDaniel Gioeli
Apr 20, 2013·Cancer Letters·Kiran Mahajan, Nupam P Mahajan
Mar 6, 2016·Trends in Endocrinology and Metabolism : TEM·Matthew J Schiewer, Karen E Knudsen
Nov 8, 2015·Nucleic Acids Research·Kiran Mahajan, Nupam P Mahajan
Sep 27, 2014·International Journal of Cancer. Journal International Du Cancer·Jiannan ZhangJianwei Ge
Jun 17, 2016·Molecular & Cellular Oncology·Gwenola ManicIlio Vitale
Jun 2, 2015·Cytokine & Growth Factor Reviews·Shirley K KnauerOliver H Krämer
Sep 24, 2014·BioMed Research International·Enea Gino Di DomenicoFiorentina Ascenzioni
Dec 2, 2014·Expert Opinion on Therapeutic Targets·Dian-Na GuLing Tian
Sep 1, 2016·Journal of Cancer Research and Clinical Oncology·Nisintha MahendrarajahOliver H Krämer
May 31, 2018·Molecular Oncology·Christianne HoeyStanley K Liu
Aug 26, 2014·The Journal of Biological Chemistry·Kiran MahajanNupam P Mahajan
Feb 2, 2018·Scientific Reports·Nupam P MahajanKiran Mahajan
Apr 4, 2013·American Journal of Physiology. Endocrinology and Metabolism·Alejandro S GodoyGary J Smith
Nov 28, 2019·BioMed Research International·Xia LiuBaolin Han
Jul 19, 2018·Science Signaling·Chelsea JenkinsJeffrey W Tyner
Dec 4, 2020·JCI Insight·Jae Yoon JeonSharyn D Baker
Oct 14, 2020·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Jiajia GuShi-Yong Sun
Jul 10, 2018·Biochimica Et Biophysica Acta. Reviews on Cancer·Rama SoundararajanSendurai A Mani
Nov 15, 2015·Journal of Cell Science·Poorwa AwasthiAmit Kumar
Feb 24, 2015·Journal of Medicinal Chemistry·Harshani R LawrenceNicholas J Lawrence

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