Metabolic Inhibition of Anaplastic Thyroid Cancer with 3-BP Depends on Hexokinase II Expression
Abha Aggarwal, Sonia Aggarwal, Benjamin Pollard, and Matthew A. Nehs
Brigham and Women's Hospital Boston, MA USA
Background: Anaplastic thyroid cancer (ATC) is a fatal malignancy, and current therapies are ineffective. The glycolytic enzyme Hexokinase II (HK2) is over expressed in many cancers and represents a potential novel target. We therefore hypothesized that inhibition of hexokinase II with 3-bromopyruvate (3BP) would inhibit cell proliferation in ATC cell lines.
Methods: We performed cell proliferation assays using 3 ATC cell-lines (8505c, JL16, and JL30) and one thyroid cancer cell line (TPC-1). We cultured the cell-lines in high (25uM) or low (3uM) glucose concentrations with the administration of 200uM of 3BP with or without supplemental Betahydroxybutarate (BHB). We analyzed HK2 expression by Fluorescent in-situ hybridization (FISH). Continuous variables were analyzed by One-way ANOVA and Studentís T tests.
Results: We found that 3BP significantly inhibited proliferation in cell lines that over expressed HK2 (JL30 and TPC-1) (P<0.002) but did not significantly inhibit proliferation in the cell lines with low HK2 expression (8505c and JL16). A low glucose environment significantly decreased proliferation in JL30 and TPC-1 (p<0.02), but not JL16 or 8505c cells. The combination of 3BP, BHB, and a low glucose environment significantly decreased proliferation in all four cell lines (p<0.01).
Conclusion: ATC proliferation was inhibited by 3BP in cells lines that overexpress HK2. This effect was augmented with the addition of BHB and a low glucose environment. Further studies are warranted to see if metabolic inhibition of glycolysis with 3BP, BHB, and a low glucose environment may be an effective treatment for anaplastic thyroid carcinoma.
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