Proteomic Comparison and MRM-Based Comparative Analysis of Metabolites Reveal Metabolic Shift in Human Prostate Cancer Cell Lines

One of the major
challenges in prostate cancer therapy remains
the development of effective treatments for castration-resistant prostate
cancer (CRPC), as the underlying mechanisms for its progression remain
elusive. Previous studies showed that androgen receptor (AR) is crucially
involved in regulation of metabolism in prostate cancer (PCa) cells
throughout the transition from early stage, androgen-sensitive PCa
to androgen-independent CRPC. AR achieves such metabolic rewiring
directively either via its transcriptional activity or via interactions
with AMP-activated protein kinase (AMPK). However, due to the heterogeneous
expression and activity status of AR in PCa cells, it remains a challenge
to investigate the links between AR status and metabolic alterations.
To this end, we compared the proteomes of three pairs of androgen-sensitive
(AS) and androgen-independent (AI) PCa cell lines, namely, PC3-AR+/PC3, 22Rv1/Du145, and LNCaP/C42B, using an iTRAQ labeling
approach. Our results revealed that most of the differentially expressed
proteins between each pair function in metabolism, indicating a metabolic
shift between AS and AI cells, as further validated by multiple reaction
monitoring (MRM)-based quantification of nucleotides and relative
comparison of fatty acids between these cell lines. Furthermore, increased
adenylate kinase isoenzyme 1 (AK1) in AS relative to AI cells may
result in activation of AMPK, representing a major regulatory factor
involved in the observed metabolic shift in PCa cells.