Modified Shenqi Dihuang Decoction inhibits prostate cancer metastasis by disrupting TCA cycle energy metabolism via NF-kB/p65-mediated OGDH regulation

Abstract

Background

Prostate cancer (PCa) is a significant malignancy in men, particularly challenging in the metastatic stage due to poor prognosis and limited treatment efficacy. Traditional Chinese Medicine, particularly Modified Shenqi Dihuang Decoction (MSDD), has demonstrated promise in inhibiting PCa metastasis, although its mechanisms remain unclear.

Methods

The efficacy of MSDD was evaluated using migration assays and a nude mouse model. Metabolomics was employed to identify the biological processes affected by MSDD. Systematic pharmacology, bioinformatics, and molecular dynamics were utilized to determine direct action targets of MSDD. Additionally, luciferase reporter assays, ChIP-qPCR, and gene editing were applied to elucidate the pharmacological mechanisms.

Results

MSDD effectively inhibited prostate metastasis both in vivo and in vitro, without significant adverse events reported. Metabolomics and molecular biology experiments indicated that MSDD transcriptionally represses OGDH, affecting energy metabolism associated with the tricarboxylic acid cycle (TCA) in PCa. The active components of MSDD were found to potentially bind to the transcription factor RELA (NF-kB-p65), and further experiments demonstrated that RELA regulates OGDH transcription. Further experiments revealed that the anti-metastatic effects of MSDD are RELA-dependent, indicating the crucial role of the NF-kB/OGDH axis in this process.

Conclusions

These findings support the clinical use of MSDD in metastatic PCa, emphasizing its potential to address current treatment gaps. The identified NF-kB/OGDH-dependent mechanism not only underpins MSDD's anti-metastatic effects but also reflects OGDH as a potential therapeutic target. Further research into the role of TCA in PCa progression is imperative.