HKDC1 C-terminal based peptides inhibit extranodal natural killer/T-cell lymphoma by modulation of mitochondrial function and EBV suppression

Abstract

Extranodal nasal-type natural killer/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma that progresses rapidly and relapses frequently. Advanced ENKTL is multidrug chemoresistant and has a poor prognosis. In this study, we aim to develop a novel hexokinase domain component 1 (HKDC1)-based antitumor target for ENKTL that is involved with the antimetabolic signaling pathway, EBV replication, and P-glycoprotein (P-gp) expression. We showed that HKDC1 is highly upregulated in ENKTL cells and HKDC1 knockdown significantly suppresses ENKTL tumor growth. In addition, HKDC1 is highly identical with four other hexokinase isoforms, with the only difference being in the last eight amino acids (aa) at the C-terminal. Further investigation showed that peptide delivery of the last eight aa of HKDC1 at the Cterminal (HKC8) with D-configuration using transferrin (Tf) receptor internalization sequence (Tf-D-HKC8) inhibits HKDC1 association with vascular endothelial growth factor 1 (VDAC1), resulting in mitochondrial dysfunction and reactive oxygen species (ROS) overgeneration and subsequently suppressing EBV replication and P-gp expression, making it very effective in killing EBV-positive ENKTL cells. Further in vivo experiments showed that local injection of Tf-D-HKC8 peptide significantly suppresses ENKTL tumor growth and EBV replication in ENKTL xenograft mouse models. We conclude that HKDC1 C-terminal-based peptides inhibit ENKTL by modulation of mitochondrial function and EBV suppression.

HKDC1 promotes the tumorigenesis and glycolysis in lung adenocarcinoma via regulating AMPK/mTOR signaling pathway

“…HKDC1 affects behavioral functions in cancers by different mechanisms. For instance, Chen et al discovered that HKDC1 knockdown significantly suppressed extranodal nasal-type natural killer/T-cell lymphoma growth through ROS generation and DNA damage [21]. Zhang et al found that silencing HKDC1 may inhibit cellular proliferation and migration by suppressing Wnt/β-catenin signaling pathway in HCC [22].…”

“…For example, overexpression of HKDC1 could lead to the metabolic dysfunction of hepatocytes, which may be associated with nonalcoholic fatty liver disease [20]. In addition, increasing evidence shows that HKDC1 may play oncogenic roles in cancers, such as lymphoma [21], liver cancer [22], breast cancer [23] and colorectal cancer [24], indicating that HKDC1 may serve as a therapeutic target in cancers.…”

Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study

“…Importantly, targeting hexokinase domain component 1 (HKDC1), which is highly expressed in ENKTL, is associated with mitochondrial dysfunction and oxidative stress, EBV replication, and P-glycoprotein (P-gp) expression. 152 The above studies further clarify the role of mitochondria-related cell death in the EBV tumorigenesis process, which will help us to fully understand the molecular mechanism of mitochondria in the pathogenesis of EBV-related tumors, and will be beneficial to the discovery and application of targeted drugs.…”

Latent Membrane Protein 1 Promotes Tumorigenesis Through Upregulation of PGC1β Signaling Pathway

“…Similarly, HKDC1, another novel HK isoform, has been recently found to play a potential role in tumorigenesis through glucose homeostasis and oxidative stress [26,[30][31][32][33]. In addition, we recently found that HKDC1 C-terminal based peptides inhibited NKTCL by modulating the mitochondrial function and suppressing EBV [34]; however, the detailed mechanism remains unclear.…”