Oncotarget

Research Papers:

Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer

Marybeth Anderson _, Raoud Marayati, Richard Moffitt and Jen Jen Yeh

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Oncotarget. 2017; 8:56081-56094. https://doi.org/10.18632/oncotarget.9760

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Abstract

Marybeth Anderson1,2, Raoud Marayati2, Richard Moffitt2 and Jen Jen Yeh1,2,3

1Curriculum in Genetics & Molecular Biology, The University of North Carolina, Chapel Hill, NC

2Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC

3Departments of Surgery and Pharmacology, The University of North Carolina, Chapel Hill, NC

Correspondence to:

Jen Jen Yeh, email: [email protected]

Keywords: pancreatic cancer, hexokinase 2, glycolysis, metastasis

Received: January 19, 2016    Accepted: May 02, 2016    Published: June 01, 2016

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a KRAS-driven cancer with a high incidence of metastasis and an overall poor prognosis. Previous work in a genetically engineered mouse model of PDAC showed glucose metabolism to be important for maintaining tumor growth. Multiple glycolytic enzymes, including hexokinase 2 (HK2), were upregulated in primary PDAC patient tumors, supporting a role for glycolysis in promoting human disease. HK2 was most highly expressed in PDAC metastases, suggesting a link between HK2 and aggressive tumor biology. In support of this we found HK2 expression to be associated with shorter overall survival in PDAC patients undergoing curative surgery. Transient and stable knockdown of HK2 in primary PDAC cell lines decreased lactate production, anchorage independent growth (AIG) and invasion through a reconstituted matrix. Conversely, stable overexpression of HK2 increased lactate production, cell proliferation, AIG and invasion. Pharmacologic inhibition of lactate production reduced the HK2-driven increase in invasion while addition of extracellular lactate enhanced invasion, together providing a link between glycolytic activity and metastatic potential. Stable knockdown of HK2 decreased primary tumor growth in cell line xenografts and decreased incidence of lung metastasis after tail vein injection. Gene expression analysis of tumors with decreased HK2 expression showed alterations in VEGF-A signaling, a pathway important for angiogenesis and metastasis, consistent with a requirement of HK2 in promoting metastasis. Overall our data provides strong evidence for the role of HK2 in promoting PDAC disease progression, suggesting that direct inhibition of HK2 may be a promising approach in the clinic.


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