Abstract
BackgroundMannose, a natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI). However, its function in thyroid cancer still remains elusive.MethodsMTT, colony formation and flow cytometry assays were performed to determine the response of thyroid cancer cells to mannose. Meanwhile, mouse models of subcutaneous xenograft and primary papillary thyroid cancer were established to determine in vivo anti-tumor activity of mannose. The underlying mechanism of mannose selectively killing thyroid cancer cells was clarified by a series of molecular and biochemical experiments.ResultsOur data demonstrated that mannose selectively suppressed the growth of thyroid cancer cells, and found that enzyme activity of PMI rather than its protein expression was negatively associated with the response of thyroid cancer cells to mannose. Besides, our data showed that zinc ion (Zn2+) chelator TPEN clearly increased the response of mannose-insensitive cells to mannose by inhibiting enzyme activity of PMI, while Zn2+ supplement could effectively reverse this effect. Further studies found that the expression of zinc transport protein ZIP10, which transport Zn2+ from extracellular area into cells, was negatively related to the response of thyroid cancer cells to mannose. Knocking down ZIP10 in mannose-insensitive cells significantly inhibited in vitro and in vivo growth of these cells by decreasing intracellular Zn2+ concentration and enzyme activity of PMI. Moreover, ectopic expression of ZIP10 in mannose-sensitive cells decrease their cellular response to mannose. Mechanistically, mannose exerted its anti-tumor effect by inhibiting cellular glycolysis; however, this effect was highly dependent on expression status of ZIP10.ConclusionThe present study demonstrate that mannose selectively kills thyroid cancer cells dependent on enzyme activity of PMI rather than its expression, and provide a mechanistic rationale for exploring clinical use of mannose in thyroid cancer therapy.
Highlights
Mannose, a natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI)
The results showed that the proliferation of Hthy-ori3–1 cells was hardly affected by mannose (Additional file 2: Fig. S1), suggesting that mannose is a safe agent for the treatment of thyroid cancer
Ectopic expression of Zinc transporter 10 (ZIP10) in mannosesensitive cells decrease their response to mannose. These findings indicate that expression status of ZIP10 is a major determinant for anti-tumor activity of mannose in thyroid cancer cells, and may be a potential therapeutic target to sensitize the response of cancer cells to mannose
Summary
A natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI). There are still minority patients who relapse and develop into undifferentiated thyroid cancer, which are resistant to most conventional therapy, resulting in poor prognosis and fatal outcomes [6]. A previous study proved that mannose could change the intestinal flora, thereby improving energy metabolism. It is considered as a potential weight-loss medicine [14]. A previous study showed that higher concentration of plasma mannose predicted better prognosis for patients with esophageal adenocarcinoma [15]. It has been revealed that mannose preferentially killed cancer cells which expressed lower phosphate mannose isomerase (PMI) [16]
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