Linked Hexokinase and Glucose-6-Phosphatase Activities Reflect Grade of Ovarian Malignancy
Malignant cells exhibit increased rates of aerobic glycolysis. Here, we tested whether the accumulation of fluoro-deoxyglucose-6-phosphate (FDG6P) in ovarian cancers of differential malignancy reflects inversely correlated elevations of hexokinase (HK) and glucose-6-phosphatase (G6Pase) activities.
Twenty-nine women with suspected ovarian cancer had positron emission tomography (PET) prior to surgery. From fresh-frozen tissue, we determined the activities of HK and G6Pase, and from the PET images, we determined the tumor maximum standardized uptake value (SUVmax) of 2-deoxy-2-[18F]fluoro-D-glucose.
The SUVmax of malignant lesions significantly exceeded the SUVmax of benign (p < 0.005) and borderline lesions (p < 0.0005) that did not differ significantly. We found no significant correlation between measured HK or G6Pase activities and histological tumor type or SUVmax except that G6Pase activities were higher in malignant than borderline lesions (p < 0.05). Measured HK and G6Pase activities correlated inversely (p < 0.05). The slopes from the regression lines of the three correlations yielded positively correlated abscissa and ordinate intercepts, designated HKmax and G6Pasemax, respectively (r = 0.67, p < 0.0001). The positive correlations between the abscissa and ordinate intercepts with SUVmax had regression coefficients of r = 0.44, p < 0.05; and r = 0.39, p < 0.05, respectively.
The results distinguished two ovarian cancer phenotypes, one with elevated HK activity and low G6Pase activity, and another with the opposite characteristics.
Key WordsOvarian cancer FDG Glucose-6-phosphatase Hexokinase Positron emission tomography (PET)
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Twenty-three patients were enrolled prospectively after both oral and written information and signed consent. Six patients were enrolled retrospectively, with previously obtained formal consent to retroactive use of tissue still valid.
- 4.Nakamura K, Hongo A, Kodama J, Hiramatsu Y (2012) The pretreatment of maximum standardized uptake values (SUVmax) of the primary tumor is predictor for poor prognosis for patients with epithelial ovarian cancer. Acta Med Okayama 66:53–60Google Scholar
- 8.Kurokawa T, Yoshida Y, Kawahara K, Tsuchida T, Okazawa H, Fujibayashi Y, Yonekura Y, Kotsuji F (2004) Expression of GLUT-1 glucose transfer, cellular proliferation activity and grade of tumor correlate with [F-18]-fluorodeoxyglucose uptake by positron emission tomography in epithelial tumors of the ovary. Int J Cancer 109:926–932CrossRefGoogle Scholar
- 9.Yen TC, See LC, Lai CH, Yah-Huei CW, Ng KK, Ma SY, Lin WJ, Chen JT, Chen WJ, Lai CR, Hsueh S (2004) 18F-FDG uptake in squamous cell carcinoma of the cervix is correlated with glucose transporter 1 expression. J Nucl Med 45:22–29Google Scholar
- 10.Nagamatsu A, Umesaki N, Li L, Tanaka T (2010) Use of 18F-fluorodeoxyglucose positron emission tomography for diagnosis of uterine sarcomas. Oncol Rep 23:1069–1076Google Scholar
- 20.Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, Verzijlbergen FJ, Barrington SF, Pike LC, Weber WA, Stroobants S, Delbeke D, Donohoe KJ, Holbrook S, Graham MM, Testanera G, Hoekstra OS, Zijlstra J, Visser E, Hoekstra CJ, Pruim J, Willemsen A, Arends B, Kotzerke J, Bockisch A, Beyer T, Chiti A, Krause BJ, European Association of Nuclear Medicine (EANM) (2015) FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging 42:328–354CrossRefGoogle Scholar
- 22.Taussky HH, Shorr E (1953) A microcolorimetric method for the determination of inorganic phosphorus. J Biol Chem 202:675–685Google Scholar
- 26.Jin Z, Gu J, Xin X, Li Y, Wang H (2014) Expression of hexokinase 2 in epithelial ovarian tumors and its clinical significance in serous ovarian cancer. Eur J Gynaecol Oncol 35:519–524Google Scholar
- 28.Gejl M, Egefjord L, Lerche S, Vang K, Bibby BM, Holst JJ, Mengel A, Møller N, Rungby J, Brock B, Gjedde A (2012) Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia. J Cereb Blood Flow Metab 32:2146–2152CrossRefGoogle Scholar
- 33.Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, Robey RB, Hay N (2013) Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24:213–228CrossRefGoogle Scholar