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Published on: February 27, 2015
Proteomic Comparison and MRM-Based Comparative Analysis of Metabolites Reveal Metabolic Shift in Human Prostate
Qingbo Shu1, Tanxi Cai, Xiulan Chen
1‡University of Chinese Academy of Sciences, Beijing 100049, China.
Abstract:
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.
Insights
Metabolic reprogramming is key in prostate cancer (PCa) progression. This study reveals significant metabolic shifts between androgen-sensitive and castration-resistant prostate cancer cells, identifying adenylate kinase isoenzyme 1 (AK1) as a potential regulator.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Castration-resistant prostate cancer (CRPC) presents a major therapeutic challenge due to poorly understood progression mechanisms.
- Androgen receptor (AR) critically regulates metabolism in prostate cancer (PCa) cells during the transition from androgen-sensitive (AS) to CRPC.
- Investigating AR's role in metabolic alterations is complex due to heterogeneous AR expression and activity in PCa cells.
Purpose of the Study:
- To compare the proteomes of matched androgen-sensitive (AS) and androgen-independent (AI) prostate cancer cell lines.
- To identify metabolic differences associated with the transition from AS to AI prostate cancer.
- To explore the role of adenylate kinase isoenzyme 1 (AK1) and AMP-activated protein kinase (AMPK) in prostate cancer metabolic shifts.
Main Methods:
- Utilized iTRAQ labeling for comparative proteomic analysis of three AS/AI PCa cell line pairs (PC3-AR(+)/PC3, 22Rv1/Du145, LNCaP/C42B).
- Employed multiple reaction monitoring (MRM) for nucleotide quantification.
- Performed relative fatty acid comparisons between cell line pairs.
Main Results:
- Proteomic analysis revealed that most differentially expressed proteins between AS and AI cells are involved in metabolism, indicating a significant metabolic shift.
- Nucleotide and fatty acid analyses further validated the metabolic alterations associated with the AS to AI transition.
- Increased adenylate kinase isoenzyme 1 (AK1) expression was observed in AS cells compared to AI cells, suggesting a link to AMPK activation.
Conclusions:
- A distinct metabolic shift occurs during prostate cancer progression from androgen-sensitive to castration-resistant states.
- Adenylate kinase isoenzyme 1 (AK1) may play a crucial role in mediating metabolic rewiring in prostate cancer, potentially via AMPK activation.
- Understanding these AR-regulated metabolic changes offers potential therapeutic targets for CRPC.
