Interaction between AR signalling and CRKL bypasses casodex inhibition in prostate cancer.
The underlying mechanism of failed androgen ablation therapy is unknown. It is recognised that under therapeutic conditions the androgen receptor (AR) remains functionally active independent of hormone stimulation and may function through an alternative pathway. We report a novel cooperative interaction between CRKL (an intracellular signalling adaptor protein) and the AR. We demonstrate by biochemical and genetic approaches that CRKL is associated with the AR complex and is localised in the nucleus of prostate cancer cells and patient tissue biopsies. The interaction between CRKL and the AR is functionally relevant as demonstrated by its presence on the enhancer region of an androgen regulated gene (human Kallikrein-2), its upregulation of PSA, and reduction in AR transactivation following its disruption by siRNA knockdown. In the presence of the AR inhibitor casodex, the expression of CRKL co-stimulated by growth factors is able to rescue AR activity independent of hormone. Our data provides insight on how a non-nuclear factor such as CRKL may interact with the AR complex to bypass hormone dependency by using an alternative growth factor signalling pathway in advanced prostate cancer.
Reebye
Vikash
V
Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Bevan
Charlotte L
CL
Nohadani
Mahrokh
M
Hajitou
Amin
A
Habib
Nagy A
NA
Mintz
Paul J
PJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009570:Nitriles / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014105:Tosyl Compounds / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D000728:Androgens; D000813:Anilides; C082869:CRKL protein; D009570:Nitriles; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide