Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

[1]  S. Ellard,et al.  A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer , 2012, Investigational New Drugs.

[2]  H. Inui,et al.  Androgen deprivation causes truncation of the C‐terminal region of androgen receptor in human prostate cancer LNCaP cells , 2012, Cancer science.

[3]  P. Nelson,et al.  The androgen/androgen receptor axis in prostate cancer , 2012, Current opinion in oncology.

[4]  Yingming Li,et al.  Androgen Receptor Splice Variants Activate Androgen Receptor Target Genes and Support Aberrant Prostate Cancer Cell Growth Independent of Canonical Androgen Receptor Nuclear Localization Signal* , 2012, The Journal of Biological Chemistry.

[5]  Daniel Gioeli,et al.  Post-translational modification of the androgen receptor , 2012, Molecular and Cellular Endocrinology.

[6]  A. Hobisch,et al.  Sorafenib decreases proliferation and induces apoptosis of prostate cancer cells by inhibition of the androgen receptor and Akt signaling pathways , 2012, Endocrine-related cancer.

[7]  K. Spindler,et al.  IκB kinases modulate the activity of the androgen receptor in prostate carcinoma cell lines. , 2012, Neoplasia.

[8]  M. Höpfner,et al.  AR-Q640X, a model to study the effects of constitutively active C-terminally truncated AR variants in prostate cancer cells , 2012, World Journal of Urology.

[9]  P. Nelson,et al.  Androgen Receptor Variants Occur Frequently in Castration Resistant Prostate Cancer Metastases , 2011, PloS one.

[10]  M. Cronauer,et al.  Inhibition of Glycogen Synthase Kinase-3β Counteracts Ligand-Independent Activity of the Androgen Receptor in Castration Resistant Prostate Cancer , 2011, PloS one.

[11]  P. Nelson,et al.  Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice Variants , 2011, Clinical Cancer Research.

[12]  M. Sadar,et al.  Androgen receptor and its splice variants in prostate cancer , 2011, Cellular and Molecular Life Sciences.

[13]  N. Socci,et al.  Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor , 2010, Proceedings of the National Academy of Sciences.

[14]  D. Grandér,et al.  Sorafenib induces apoptosis and autophagy in prostate cancer cells in vitro. , 2010, International journal of oncology.

[15]  H. Zeng,et al.  The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells. , 2010, Asian journal of andrology.

[16]  M. Cronauer,et al.  Inhibition of glycogen synthase kinase‐3β promotes nuclear export of the androgen receptor through a CRM1‐dependent mechanism in prostate cancer cell lines , 2010, Journal of cellular biochemistry.

[17]  G. Sonpavde,et al.  Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[18]  S. Steinberg,et al.  Final analysis of a phase II trial using sorafenib for metastatic castration‐resistant prostate cancer , 2009, BJU international.

[19]  P. Kantoff,et al.  Phase II study of sunitinib in men with advanced prostate cancer. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  X. Liu,et al.  Target gene-specific regulation of androgen receptor activity by p42/p44 mitogen-activated protein kinase. , 2008, Molecular endocrinology.

[21]  M. Gleave,et al.  Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. , 2008, Cancer research.

[22]  R. Hautmann,et al.  Inhibition of glycogen synthase kinase-3 in androgen-responsive prostate cancer cell lines: are GSK inhibitors therapeutically useful? , 2008, Neoplasia.

[23]  S. Steinberg,et al.  A Phase II Clinical Trial of Sorafenib in Androgen-Independent Prostate Cancer , 2008, Clinical Cancer Research.

[24]  D. Strumberg,et al.  A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV , 2007, British Journal of Cancer.

[25]  P. Thall,et al.  Platelet-Derived Growth Factor Receptor Inhibition and Chemotherapy for Castration-Resistant Prostate Cancer with Bone Metastases , 2007, Clinical Cancer Research.

[26]  C. Tepper,et al.  Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. , 2007, Cancer research.

[27]  N. Moore,et al.  Steroid receptor phosphorylation: a key modulator of multiple receptor functions. , 2007, Molecular endocrinology.

[28]  D. Jacqmin,et al.  Unexpected paracrine action of prostate cancer cells harboring a new class of androgen receptor mutation—A new paradigm for cooperation among prostate tumor cells , 2007, International journal of cancer.

[29]  C. Suschek,et al.  Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression , 2007, Oncogene.

[30]  G. Bubley,et al.  Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1 , 2006, Proceedings of the National Academy of Sciences.

[31]  D. Feldman,et al.  The development of androgen-independent prostate cancer , 2001, Nature Reviews Cancer.

[32]  J. Moul,et al.  Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. , 1994, Cancer research.

[33]  T. Mosmann Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[34]  A. Armstrong,et al.  Dasatinib combined with docetaxel for castration‐resistant prostate cancer , 2012, Cancer.

[35]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[36]  M. Safarinejad Safety and efficacy of sorafenib in patients with castrate resistant prostate cancer: a Phase II study. , 2010, Urologic oncology.

[37]  R. Vessella,et al.  Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. , 2009, Cancer research.

[38]  L. Seymour,et al.  A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[39]  D. Chopin,et al.  Constitutive activation of the androgen receptor by a point mutation in the hinge region: A new mechanism for androgen‐independent growth in prostate cancer , 2004, International journal of cancer.

[40]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[41]  P. Stattin,et al.  Expression of Androgen Receptor Splice Variants in Prostate Cancer Bone Metastases is Associated with Castration-Resistance and Short Survival , 2011, PloS one.