Taxanes Inhibit the Microtubule-Dependent Androgen Receptor Trafficking and Signalling in Prostate Cancer.

Prostate cancer is the most commonly diagnosed malignancy in males in the United States and its progression depends on active androgen receptor (AR) signalling. Androgen deprivation therapy provides palliation but not cure, and the disease progresses to castration-resistant prostate cancer (CRPC). The taxanes represent the most effective class of anti-tumour agents that improve survival in CRPC patients. However, their benefits are transient and nearly all patients eventually progress. Understanding the molecular basis of taxane activity in prostate cancer is imperative for establishing successful treatment of this disease. The work in this study shows that AR associates with microtubules and that taxanes impair the ligand-induced nuclear accumulation of AR. Furthermore, co-immunoprecipitation assays and confocal microscopy revealed that AR trafficking towards the nucleus occurs along microtubules with the aid of the dynein motor protein. These results have been extended to two clinically relevant, ligand-independent AR splice variants, ARv567 and AR-V7. Live cell imaging experiments showed that ARv567 is dependent on microtubules in the same way as the full-length receptor, as pretreatment with microtubule-targeting drugs abrogated nuclear accumulation of both. However, this does not apply to the AR-V7 variant, which is not under microtubule control and remains insensitive to taxane treatment. Furthermore, the results show that ARv567, but not AR-V7, associates with microtubules as evidenced by microtubule cosedimentation assays and requires dynein for its nuclear translocation. In addition, deletion mutants of the AR show that the DNA binding domain and hinge region of the receptor are important for microtubule binding. Taken together, these data suggest that inhibition of AR nuclear accumulation underlies, in part, the activity of taxanes in CRPC revealing a new mechanism of action for this class of drugs and that the presence of AR splice variants may determine the clinical efficacy of taxane chemotherapy

Taxanes inhibit the microtubule-dependent androgen receptor trafficking and signalling in prostrate cancer

Prostate cancer is the most commonly diagnosed malignancy in males in the United States and its, progression depends on active androgen receptor (AR) signalling. Androgen deprivation therapy provides palliation but not cure, and the disease progresses to castration-resistant prostate cancer (CRPC). The taxanes represent the most effective class of anti-tumour agents that improve survival in CRPC patients. However, their benefits are transient and nearly all patients eventually progress. Understanding the molecular basis of taxane activity in prostate cancer is imperative for establishing successful treatment of this disease. The work in this study shows that AR associates with microtubules and that taxanes impair the ligand-induced nuclear accumulation of AR. Furthermore, co-immunoprecipitation assays and confocal microscopy revealed that AR trafficking towards the nucleus occurs along microtubules with the aid of the dynein motor protein. These results have been extended to two clinically relevant, ligand- independent AR splice variants, ARv567 and AR-V7. Live cell imaging experiments showed that ARv567 is dependent on microtubules in the same way as the full-length receptor, as pretreatment with microtubule-targeting drugs abrogated nuclear accumulation of both. However, this does not apply to the AR-V7 variant, which is not under microtubule control and remains insensitive to taxane treatment. Furthermore, the results show that ARv567, but not AR- V7, associates with microtubules as evidenced by microtubule co- sedimentation assays and requires dyne in for its nuclear translocation. In addition, deletion mutants of the AR show that the DNA binding domain and hinge region of the receptor are important for microtubule binding. Taken together, these data suggest that inhibition of AR nuclear accumulation underlies, in part, the activity of taxanes in CRPC revealing a new mechanism of action for this class of drugs and that the presence of AR splice variants may determine the clinical efficacy of taxane chemotherapy.EThOS - Electronic Theses Online ServiceGBUnited Kingdo