ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase

Abstract

Background 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). However, its function in thyroid cancer still remains elusive. Methods MTT, 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. Results Our 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. Conclusion The 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.

Mannose: A Sweet Option in the Treatment of Cancer and Inflammation

“…For thyroid cancer, one recent study has found that whether the cell line is sensitive to mannose depends mainly on the enzyme activity of PMI (Ma et al, 2021). Structurally, zinc ions (Zn 2+ ) are critical for the binding of the PMI and substrate, so the enzymatic function of PMI depends on Zn 2+ concentration (Bangera et al, 2019).…”

“…ZIP10 is a Zn 2+ transporter expressed during early B cell development that transports Zn 2+ from outside the cell to the cytoplasm, thereby altering the concentration of Zn 2+ within the cell (Miyai et al, 2014). The latest study found that in thyroid cancer cells that are not sensitive to mannose, knocking down ZIP10 can significantly improve their sensitivity to mannose, and M6P accumulation in turn enhances the inhibitory effect of mannose on cellular glycolysis (Ma et al, 2021) (Figure 1). These findings suggest that mannose has potential application value in the treatment of thyroid cancer.…”

TBX1 functions as a tumor suppressor in colorectal cancer by PPP2R2B-mediated the inhibition of MAPK/ERK and PI3K/AKT signaling pathways

“…RNA isolation, cDNA preparation and qRT-PCR were performed as described previously 33 . The mRNA expressions of the indicated genes were normalized to β-actin.…”

“…Western blot analysis was similarly performed according to the previous protocol 33 . The information of the related antibodies was presented in Supplementary Table S3.…”

“…The procedures for cell proliferation, colony formation, migration, and invasion assays were similarly performed according to pervious study 33 .…”