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Targeting Sphingosine-1-Phosphate Signaling Attenuates Doxorubicin-Aggravated Bone Loss in Obese Breast Cancer Mice
Yu Zhang1,2, Hao Shen1, Junjie Niu1
1Department of Orthopedics The First Affiliated Hospital of Soochow University Orthopedic Institute of Soochow University Suzhou Jiangsu China.
Abstract:
Although chemotherapy-induced bone loss is well-recognized during breast cancer treatment, the underlying mechanism remains to be further elucidated, especially in patients with obesity. In this study, the objective was to investigate the impact of genomic silencing and pharmacological inhibition of S1P synthesis on bone loss in doxorubicin-induced obese breast cancer mice. In vitro study, upon the treatment of doxorubicin combined with palmitic acid, the S1P generated by 4T1 cells was significantly increased, resulting in an increase in osteoclastogenesis by activating the S1PR1/p-STAT3/NFATc-1 pathway in bone marrow-derived macrophages. In vivo study, pharmacological intervention with Sphingosine kinases (SPHK) antagonist SKI II or biological inhibition with SPHK1 and SPHK2 short hairpin RNA significantly reduced S1P production and rescued the obese breast cancer-bearing mice from doxorubicin-induced bone loss, manifested by the decreased osteoclastogenesis and recovered bone microarchitecture. Similarly, the administration of the S1PR1 antagonist FTY720 also alleviated bone loss in the breast cancer-bearing mice fed a high-fat diet. These studies indicate that genetic silencing and pharmacological inhibition can suppress S1P-dependent bone loss in doxorubicin-induced obese breast cancer mice. S1P shows promise as a potential drug target for preventing chemotherapy-induced bone loss in patients.
Insights
Chemotherapy can cause bone loss in obese breast cancer patients. Inhibiting Sphingosine-1-Phosphate (S1P) synthesis or its receptor S1PR1 can prevent this bone loss, offering a potential therapeutic target.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Chemotherapy-induced bone loss is a known complication in breast cancer patients, particularly those with obesity.
- The precise mechanisms driving this bone loss, especially in obese patients, require further investigation.
Purpose of the Study:
- To explore the effects of inhibiting Sphingosine-1-Phosphate (S1P) synthesis on bone loss in doxorubicin-induced obese breast cancer mouse models.
- To evaluate both genetic and pharmacological inhibition strategies for S1P synthesis and its receptor S1PR1.
Main Methods:
- In vitro: Doxorubicin and palmitic acid treatment of 4T1 cells to assess S1P production and osteoclastogenesis.
- In vivo: Administration of SPHK antagonist SKI II, SPHK1/2 shRNA, or S1PR1 antagonist FTY720 in obese breast cancer mouse models.
- Bone microarchitecture analysis and osteoclastogenesis assessment.
Main Results:
- Doxorubicin and palmitic acid increased S1P production, promoting osteoclastogenesis via the S1PR1/p-STAT3/NFATc-1 pathway in vitro.
- Pharmacological and genetic inhibition of S1P synthesis significantly reduced bone loss and improved bone microarchitecture in vivo.
- FTY720 administration also mitigated bone loss in high-fat diet-fed mice.
Conclusions:
- Sphingosine-1-Phosphate (S1P) plays a critical role in chemotherapy-induced bone loss in obese breast cancer models.
- Targeting S1P synthesis or its receptor S1PR1 presents a promising therapeutic strategy for preventing bone loss in cancer patients.
