On November 9, 2024, Professor Wang Xinghuan's team from the Department of Urology, Zhongnan Hospital of Wuhan University, published a research paper titled "Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization" in Communications Biology (a top journal in the first zone of the Chinese Academy of Sciences).
The progression of bladder cancer or extravesical metastasis will seriously affect the prognosis and quality of life of patients. Lipid metabolism disorder is one of the most prominent metabolic alterations in cancer, and the mevalonate pathway is an important route for cholesterol synthesis in the body. Our research group previously found through sequencing of bladder cancer tissues, Mendelian randomization analysis, and a series of cell and animal experiments that the mevalonate pathway is associated with the progression of bladder cancer[1-2] , but the specific mechanism of action remains to be further explored.
This study utilized tissue and single-cell sequencing datasets of common urinary system tumors (such as bladder cancer, prostate cancer, clear cell renal cell carcinoma, papillary renal cell carcinoma, etc.) to systematically analyze the genetic variations, copy number alterations, and mRNA expression of enzymes related to the mevalonate pathway among different tumors. It was found that the elevated expression of enzymes related to the mevalonate pathway in bladder cancer is associated with poor prognosis for patients.
Knocking down the key enzyme FDPS in the mevalonate pathway or inhibiting the mevalonate pathway with zoledronic acid and simvastatin in bladder cancer cells can both suppress the metastatic ability of bladder cancer cells. Notably, this inhibitory effect can be reversed by adding GGPP, a metabolic product of the mevalonate pathway, but not by adding FPP or cholesterol. Meanwhile, it was confirmed that RhoB, a member of the Rho GTPase family, is a key effector molecule regulated by the mevalonate pathway in bladder cancer metastasis. Mechanistically, inhibition of the mevalonate pathway leads to a reduction in GGPP synthesis and its mediated geranylgeranylation modification of RhoB protein, promoting an increase in RhoB protein content and thereby hindering the membrane localization of integrin β1.
In summary, this study elucidates the important role of mevalonate pathway and its key effector RhoB in bladder cancer metastasis, and provides a basis for preliminary research on mevalonate pathway related enzymes and their inhibitors as potential targets or drugs for bladder cancer treatment. The research was supported by the National Natural Science Foundation of China, the special fund for basic scientific research of central universities and the research fund of Zhongnan Hospital of Wuhan University.
References:
[1] Wang G, et al. Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway. Sci Rep. 2016, 6:35783.
[2] Wei H, et al. Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer: a comprehensive analysis using Mendelian randomization, animal models, and transcriptomics. Pharmacogenomics J. 2024, 24(5):24.
Links:
https://www.nature.com/articles/s42003-024-07067-8