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

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.

Hexokinase 2 is dispensable for photoreceptor development but is required for survival during aging and outer retinal stress

“…Despite HK2 expression being associated with increased aerobic glycolysis, we were unable to detect any significant perturbations to aerobic glycolysis in photoreceptors lacking HK2. 40,41 For example, lactate is almost exclusively produced by photoreceptors in the retina through aerobic glycolysis, however no significant changes in steady-state lactate production were observed in the Hk2 cKO retinas. 39 Furthermore, very few changes were observed in the expression of genes involved in central glucose metabolism.…”

Transforming growth factor beta‐induced, an extracellular matrix interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration

“…A recent study exploring the metabolic differences between primary PDAC and matched metastasis demonstrated in the latter a robust overexpression of several glycolytic genes, mainly GLUT1 . Interestingly, hexokinase‐2 was shown as necessary for invasion in PDAC cell lines, underlying the importance of impairing glycolysis in PDAC progression. Because, TGFBI was initially identified as an accessible tumor‐associated protein, our present work pointed out this ECM tumor‐associated protein, barely or not expressed in normal tissue, as a potential target for PDAC therapy.…”

Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond

“…For example, expression of hexokinase 2 (HK2), the embryonic isoform of hexokinase, has been linked with later tumor stages, increased risk of recurrence, and adverse clinical outcome for breast cancer, pancreatic cancer, and neuroblastoma patients . In vitro studies also support the role of HK2 in metastasis: knockdown of HK2 in Kirsten rat sarcoma viral oncogene (KRAS)‐driven pancreatic ductal adenocarcinoma (PDAC) cell lines or HK2‐overexpressing neuroblastoma cells decreased xenograft tumor growth and incidence of lung metastases in mice . However, it is not clear whether HK2 plays a specific role in promoting metastasis, or simply supports tumor growth and progression in general.…”