High expression of hexokinase 2 promotes lung cancer proliferation and metastasis

High metabolic plasticity, as one of the hallmarks of multiple cancers, usually promotes cancer growth and metastasis. Therefore, metabolic enzymes could be selective targets in suppressing the growth and invasion of cancer cells. It is generally believed that hexokinase 2 (HK2) catalysing glucose into glucose-6-phosphate is the first step in glucose metabolism. It is unclear, however, if HK2 is involved in lung cancer (LC) proliferation and metastasis.

Tumours and adjacent tissue from LC patients were used to study the expression of HK2 by RT-PCR and western blot analysis. Several different LC cell lines were used to explore the oncogene function of HK2 via MTS and BrdU assay in vitro, as well as xenografts model and Lung metastasis model in vivo.

HK2 was upregulated in primary LC tissue and metastatic foci. The expression of HK2 can be modulated by multiple mutations of oncogenes or tumour suppressors, including Kras, p53, and Keap1. Functionally, suppression of HK2 expression by shRNA transfection in LC cell lines hindered lactate production and therefore suppressed cell migration and invasion. The depletion of HK2 also sensitised the LC cells to cisplatin-induced apoptosis, suggesting that HK2 also mediated the chemoresistance in LC. Finally, our in vivo data indicated that stable knockdown of HK2 inhibited xenografted tumour growth, sensitized the tumour response to cisplatin treatment, and decreased the incidence of lung metastasis in nude mice after tail vein injection.

We demonstrated that HK2 is required for LC cell growth and metastasis in vitro and in vivo, and for its relationship between multiple mutations in LC. Our results revealed that HK2 promotes LC cell proliferation and metastasis in various mutation backgrounds of LC cells, indicating that HK2 is a high-potential therapy target for LC treatment. Our data provide strong evidence that HK2 plays an important role in promoting LC disease progression, and it may be a promising target for lung cancer therapy.