Abstract
BackgroundMetastasis is the leading cause of death in breast cancer patients. CD73, also known as ecto-5′-nucleotidase, plays a critical role in cancer development including metastasis. The existing researches indicate that overexpression of CD73 promotes growth and metastasis of breast cancer. Therefore, CD73 inhibitor can offer a promising treatment for breast cancer. Here, we determined whether tiamulin, which was found to inhibit CD73, was able to suppress breast cancer development and explored the related mechanisms.MethodsWe firstly measured the effect of tiamulin hydrogen fumarate (THF) on CD73 using high performance liquid chromatography (HPLC). Then, we investigated cell proliferation, migration and invasion in MDA-MB-231 human breast cancer cell line and 4 T1 mouse breast cancer cell line treated with THF by migration assay, invasion assay and activity assay. Besides, we examined the effect of THF on syngeneic mammary tumors of mice by immunohistochemistry.ResultsOur data demonstrated that THF inhibited CD73 by decreasing the activity instead of the expression of CD73. In vitro, THF inhibited the proliferation, migration and invasion of MDA-MB-231 and 4 T1 cells by suppressing CD73 activity. In vivo, animal experiments showed that THF treatment resulted in significant reduction in syngeneic tumor growth, microvascular density and lung metastasis rate.ConclusionsOur results indicate that THF inhibits growth and metastasis of breast cancer by blocking the activity of CD73, which may offer a promising treatment for breast cancer therapy.
Highlights
Metastasis is the leading cause of death in breast cancer patients
CD73 activity was significantly decreased by tiamulin hydrogen fumarate (THF) To investigate the effect of THF on CD73 activity, we assessed the ability of CD73 to converse Adenosine monophosphate (AMP) to Ado using high performance liquid chromatography (HPLC)
Our study revealed that THF significantly restricted breast tumor growth and metastasis, and demonstrated that the inhibition effect of THF on CD73 activity may contribute to its anti-tumor effects
Summary
CD73, known as ecto-5′-nucleotidase, plays a critical role in cancer development including metastasis. The existing researches indicate that overexpression of CD73 promotes growth and metastasis of breast cancer. Stagg et al demonstrated the ability of adenosine to increase tumor cell migration and metastasis via binding to A2B receptor [11]. CD73 could mediate cancer invasive and metastatic properties by regulating cell interaction with extracellular matrix (ECM) components, like laminin and fibronectin [16, 17]. Both enzymatic and nonenzymatic functions of CD73 are associated with cancer progression and not completely independent of each other [18]. The vital role of CD73 in cancer development has been highlighted
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