Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth

Abstract

BackgroundThe most common genetic changes identified in human NSCLC are Kras mutations (10–30 %) and p53 mutation or loss (50–70 %). Moreover, NSCLC with mutations in Kras and p53 poorly respond to current therapies, so we are trying to find a new target for the treatment strategies.MethodsFlow cytometry, crystal violet staining and immunoblotting were used to assess cell cycle arrest, proliferation and apoptosis in lung cancer cell lines after 2-DG treatment and lentivirus infection by shRNA knock down. IHC and western blotting were carried for NSG xenograft model with 2-DG treatment and lentivirus infection by shRNA knock down.ResultsKnocking down Kras down-regulated the glycolytic enzyme hexokinase II (HK2) in KP2 (mouse lung cancer cell line with Kras mutation and p53 deletion) and H23 (human lung cancer cell line with Kras mutation and p53 mutation) cell lines. Genetic studies revealed that HK2 was required for the human and mouse lung cancer cell growth in vitro and in vivo. Our pharmacological studies confirmed that 2-DG, an inhibitor of HK2, inhibited human and mouse lung cancer cell growth through inducing cell apoptosis and autophagy.ConclusionsHK2 is a promising treatment target for NSCLC with Kras activating and p53 function loss.

Glucose Metabolism Reprogrammed by Overexpression of IKKϵ Promotes Pancreatic Tumor Growth

“…Similarly, expression and activity of HK2 has been observed to be upregulated in nearly all types of cancers (32). Notably, enhanced activity of HK2 is required for the initiation and maintenance of K-Ras driven cancers, and its inhibition is shown to reduce tumor growth both in vitro and in vivo (39). There is also evidence to suggest the utility of HK2 as a prognostic marker in PDAC patients (40).…”

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

“…A glycolytic metabolism is highly correlated with tumor proliferation. Knockdown or pharmacological inhibition of glycolytic enzymes reduces growth in a variety of cancers . Forced induction of respiration has led to slower growth rates both in vitro and in vivo .…”

“…Knockdown or pharmacological inhibition of glycolytic enzymes reduces growth in a variety of cancers. [50][51][52][53] Forced induction of respiration has led to slower growth rates both in vitro and in vivo. 6,54,55 Conversely, lower oxidative phosphorylation due to mutant mitochondria increases both glycolysis and growth.…”

Effect of IDH3a on glucose uptake in lung adenocarcinoma: A pilot study based on [18F]FDG

“…HK plays a dominant role in glycolysis by promoting the coupling of ATP with glucose phosphorylation. Wang et al showed that silencing HK2 expression and inhibiting the expression of 2‐DG inhibited tumor cell proliferation and tumor growth . As a core factor of PI3K‐AKT‐mTOR signaling pathway, AKT plays a prominent role in increasing glucose uptake of tumors.…”

“…Wang et al showed that silencing HK2 expression and inhibiting the expression of 2-DG inhibited tumor cell proliferation and tumor growth. 23 As a core factor of PI3K-AKT-mTOR signaling pathway, AKT plays a prominent role in increasing glucose uptake of tumors. GSK2141795, as an AKT inhibitor, has significant antitumor effect.…”