The mevalonate pathway promotes the metastasis of osteosarcoma by regulating YAP1 activity via RhoA
Xing Du1, Yunsheng Ou1, Muzi Zhang1
1Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
Abstract:
Osteosarcoma is the most common malignant bone tumour, and the metastasis of osteosarcoma is an important cause of death. Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new target for tumour therapy. In this study, we investigated the effect of mevalonate signalling on osteosarcoma metastasis and its molecular mechanism. First, we found that the key rate-limiting enzyme of mevalonate signalling, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), was highly expressed in osteosarcoma cells, and inhibition of HMGCR with simvastatin significantly inhibited the motility of 143B cells. Next, we found that YAP1 activity was significantly upregulated in osteosarcoma cells and that YAP1 knockdown inhibited the motility of 143B cells. We also found that the mevalonate pathway regulated the motility of 143B cells by modulating YAP1 phosphorylation and cellular localization. Moreover, we found that the activity of YAP1 was regulated by the mevalonate pathway by modulating the cell membrane localization of RhoA. Finally, we demonstrated that inhibition of the mevalonate pathway notably reduced the lung metastasis of 143B cells, as reflected by the decreased incidence and number of metastatic nodules and the increased survival time of the nude mice. Taken together, our findings suggest that the mevalonate pathway can promote the metastasis of osteosarcoma by activating YAP1 via RhoA. Inhibition of the mevalonate pathway may be a promising therapeutic strategy for osteosarcoma metastasis.
Insights
The mevalonate pathway promotes osteosarcoma metastasis by activating YAP1 through RhoA. Inhibiting this pathway with simvastatin reduced tumor spread and improved survival in mice, offering a potential new therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osteosarcoma is the most common primary bone malignancy.
- Metastasis is a primary driver of mortality in osteosarcoma patients.
- The mevalonate pathway is implicated in cancer progression and presents a potential therapeutic target.
Purpose of the Study:
- To investigate the role of the mevalonate pathway in osteosarcoma metastasis.
- To elucidate the molecular mechanisms linking mevalonate signaling to osteosarcoma cell motility.
- To evaluate the therapeutic potential of targeting the mevalonate pathway for osteosarcoma metastasis.
Main Methods:
- Assessed 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) expression in osteosarcoma cells.
- Utilized simvastatin to inhibit HMGCR and assessed effects on cell motility.
- Investigated YAP1 activity, phosphorylation, and cellular localization.
- Examined the role of RhoA in mevalonate pathway-mediated cell migration.
- Evaluated the in vivo effect of mevalonate pathway inhibition on lung metastasis in a mouse model.
Main Results:
- HMGCR, the rate-limiting enzyme of the mevalonate pathway, was highly expressed in osteosarcoma.
- Simvastatin treatment significantly inhibited osteosarcoma cell motility.
- YAP1 activity was upregulated and essential for osteosarcoma cell motility.
- The mevalonate pathway regulates cell motility by modulating YAP1 phosphorylation and RhoA localization.
- Inhibition of the mevalonate pathway reduced lung metastasis and prolonged survival in mice.
Conclusions:
- The mevalonate pathway promotes osteosarcoma metastasis by activating YAP1 signaling via RhoA.
- Targeting the mevalonate pathway, potentially with statins, represents a promising therapeutic strategy to inhibit osteosarcoma metastasis.
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