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Verteporfin Suppresses YAP-Induced Glycolysis in Breast Cancer Cells
Hong Chen1, Ling-Fei Zhang2,3, Ying Miao1
1Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Objective:
The inhibition of the Hippo pathway through targeting the Yes-associated protein (YAP) presents a novel and promising approach for treating tumors. However, the efficacy of YAP inhibitors in the context of breast cancer (BC) remains incompletely understood. Here, we aimed to investigate the involvement of YAP in BC's metabolic reprogramming and reveal the potential underlying mechanisms. To this end, we assessed the function of verteporfin (VP), a YAP-TEAD complex inhibitor, on the glycolytic activity of BC cells.
Methods:
We evaluated the expression of YAP by utilizing immunohistochemistry (IHC) in BC patients who have undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) prior to biopsy/surgery. We employed RNA immunoprecipitation (RIP) and fluorescent in situ hybridization (FISH) assays to assess the interaction between YAP mRNA and human antigen R (HuR) in BC cells. The biological importance of YAP in the metabolism and malignancy of BC was evaluated in vitro. Finally, the effect of VP on glycolysis was determined by using 18F-FDG uptake, glucose consumption, and lactate production assays.
Results:
Our studies revealed that high expression of YAP was positively correlated with the maximum uptake value (SUVmax) determined by 18F-FDG PET/CT imaging in BC samples. Inhibition of YAP activity suppressed glycolysis in BC. The mechanism underlying this phenomenon could be the binding of YAP to HuR, which promotes glycolysis in BC cells. Treatment with VP effectively suppressed glycolysis induced by YAP overexpression in BC cells.
Conclusion:
VP exhibited anti-glycolytic effect on BC cells, indicating its therapeutic value as an FDA-approved drug.
Insights
Yes-associated protein (YAP) inhibition shows promise for breast cancer (BC) treatment by suppressing tumor cell glycolysis. Verteporfin (VP), a YAP inhibitor, effectively reduced BC glycolysis, highlighting its therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The Hippo pathway, regulated by Yes-associated protein (YAP), is a target for cancer therapy.
- YAP's role in breast cancer (BC) metabolic reprogramming and its therapeutic implications require further investigation.
- Understanding YAP's influence on BC metabolism can reveal novel treatment strategies.
Purpose of the Study:
- To investigate the role of YAP in metabolic reprogramming of breast cancer (BC).
- To elucidate the mechanisms by which YAP influences BC glycolysis.
- To evaluate the efficacy of verteporfin (VP), a YAP inhibitor, in targeting BC glycolysis.
Main Methods:
- Immunohistochemistry (IHC) assessed YAP expression in BC patients with pre-biopsy 18F-FDG PET/CT scans.
- RNA immunoprecipitation (RIP) and FISH assays examined YAP mRNA and HuR interactions.
- In vitro studies evaluated YAP's impact on BC metabolism and malignancy.
- 18F-FDG uptake, glucose consumption, and lactate production assays measured VP's effect on glycolysis.
Main Results:
- High YAP expression correlated positively with 18F-FDG PET/CT SUVmax in BC samples.
- YAP inhibition suppressed glycolysis in breast cancer cells.
- YAP binds to HuR, promoting glycolysis in BC cells, and VP treatment inhibited this YAP-induced glycolysis.
Conclusions:
- Verteporfin (VP) demonstrates an anti-glycolytic effect in breast cancer (BC) cells.
- VP's ability to suppress YAP-driven glycolysis suggests its therapeutic value in BC treatment.
- Targeting YAP offers a promising strategy for managing breast cancer metabolism.
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