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First published online August 18, 2009, 10.2967/jnumed.108.060780
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Journal of Nuclear Medicine Vol. 50 No. 9 1525-1532
© 2009 by Society of Nuclear Medicine
doi: 10.2967/jnumed.108.060780

Basic Science Investigation

Evaluation of the Role of Hexokinase Type II in Cellular Proliferation and Apoptosis Using Human Hepatocellular Carcinoma Cell Lines

Keun Jae Ahn1, Hee Sung Hwang2, Jeon Han Park3, Seong Hye Bang1, Won Jun Kang1, Mijin Yun1 and Jong Doo Lee1

1 Division of Nuclear Medicine, Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea; 2 Division of Nuclear Medicine, Department of Radiology, Hallym University Sacred Heart Hospital, Pyeongchon-dong, Dongan-gu, Anyang-si, Gyeonggi-do, Korea; and 3 Department of Microbiology and Brain Korea 21 Project for Medical Sciences, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea

Correspondence: For correspondence or reprints contact: Jong Doo Lee, Division of Nuclear Medicine, Department of Diagnostic Radiology, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemun-gu, Seoul, 120-752, Korea. E-mail: jdlee{at}yuhs.ac

The 18F-FDG uptake pattern on PET could be an indicator of the prognosis and aggressiveness of various tumors, including hepatocellular carcinoma (HCC). Hexokinase, especially hexokinase type II (HKII), plays a critical role in 18F-FDG uptake in rapidly growing tumors. We established a stable cell line overexpressing HKII by the transfection of full DNA of HKII to HCC cells (SNU449) that express low levels of HKII and investigated how 18F-FDG uptake mechanisms, especially overexpression of HKII, are linked to tumor proliferation mechanisms. Methods: The HKII gene was stably transfected to SNU449 cells with an expression vector. HKII expression in the cells was verified by reverse-transcriptase polymerase chain reaction, Western blot analysis, adenosine triphosphate (ATP) and lactate production, 18F-FDG uptake measurement, and confocal microscopy. Cellular proliferation activity and response to the anticancer drug cisplatin were evaluated by cell counting using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. For the evaluation of molecular pathways involved in tumor proliferation, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was investigated. Results: The stable cell line produced HKII effectively, but expression of other enzymes or transporters for glycolysis, such as glucose-6-phosphatase (G6Pase), HKI and III, and glucose transporter type 1 and 2 (Glut-1 and Glut-2), did not show any changes. 18F-FDG uptake was significantly increased after transfection. ATP and lactate production was also increased after transfection. Overexpressed HKII was associated with mitochondria on confocal microscopy. Cells with overexpression of HKII, compared with the nontransfected cell line, showed 1.5- to 2-fold higher cell survival and resistance to the anticancer agent cisplatin (2- to 8-fold). In the molecular study, the activated form of Akt was increased after transfection, and PI3K inhibitor dissociated the mitochondrial HKII to the cytoplasm. In addition, the adenosine monophosphate–activated protein kinase (AMPK) pathway is also involved in Akt signaling. Conclusion: HKII plays an important role in 18F-FDG uptake and tumor proliferation by both the PI3K-dependent and the PI3K-independent Akt signal pathways; therefore, the 18F-FDG uptake pattern on a PET scan can be a surrogate marker of prognosis in HCC.

Key Words: hepatocellular carcinoma • hexokinase • 18F-FDG uptake • PI3K/Akt signaling • prognosis

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.


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