Abstract
The androgen receptor (AR) pathway plays a central role in prostate cancer (PCa) growth and progression and is a validated therapeutic target. In response to ligand binding AR translocates to the nucleus, though the molecular mechanism is not well understood. We therefore developed multimodal Image Correlation Spectroscopy (mICS) to measure anisotropic molecular motion across a live cell. We applied mICS to AR translocation dynamics to reveal its multimodal motion. By integrating fluorescence imaging methods we observed evidence for diffusion, confined movement, and binding of AR within both the cytoplasm and nucleus of PCa cells. Our findings suggest that in presence of cytoplasmic diffusion, the probability of AR crossing the nuclear membrane is an important factor in determining the AR distribution between cytoplasm and the nucleus, independent of functional microtubule transport. These findings may have implications for the future design of novel therapeutics targeting the AR pathway in PCa.
Highlights
The androgen receptor (AR) pathway plays a central role in prostate cancer (PCa) growth and progression and is a validated therapeutic target
Dissecting AR kinetics imposes the challenges of mixed modes of motion, high spatial heterogeneity and the distinct response of agonist ligand binding
We implemented different imaging techniques at several spatiotemporal scales to assess AR intracellular motion, and integrated them with simulations to provide a dynamical picture of AR translocation at the molecular scale
Summary
The androgen receptor (AR) pathway plays a central role in prostate cancer (PCa) growth and progression and is a validated therapeutic target. Our findings suggest that in presence of cytoplasmic diffusion, the probability of AR crossing the nuclear membrane is an important factor in determining the AR distribution between cytoplasm and the nucleus, independent of functional microtubule transport These findings may have implications for the future design of novel therapeutics targeting the AR pathway in PCa. The androgen receptor (AR) regulates genes involved in the development and maintenance of the male phenotype, and plays a role in the growth and survival of prostate cancer (PCa). Taxanes have been demonstrated to bind to microtubules and prevent their disassembly, thereby suppressing microtubule dynamics and leading to mitotic arrest and apoptosis[7] This was believed to be the sole mechanism of taxane action in PCa until recently, when studies demonstrated that taxanes may act through a mechanism involving inhibition of AR nuclear translocation[8,9]. The dynamical picture of AR across different cellular compartments is still lacking, and, to the best of our knowledge, the potential presence of anisotropic AR motion has not been discussed
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