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

Qi Chen1, Jia Feng1, Jinhu Wu2

  • 1Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, 518036, PR China.

Leukemia
|March 24, 2020
PubMed

Insights

A novel peptide targeting hexokinase domain component 1 (HKDC1) effectively inhibits extranodal nasal-type natural killer/T-cell lymphoma (ENKTL) growth. This peptide suppresses Epstein-Barr virus (EBV) replication and P-glycoprotein expression by disrupting mitochondrial function.

Area of Science:

  • Oncology
  • Virology
  • Biochemistry

Background:

  • Extranodal nasal-type natural killer/T-cell lymphoma (ENKTL) is an aggressive, relapsing lymphoma associated with Epstein-Barr virus (EBV).
  • Advanced ENKTL exhibits chemoresistance and a poor prognosis, necessitating novel therapeutic strategies.
  • Hexokinase domain component 1 (HKDC1) is implicated in antimetabolic pathways, EBV replication, and P-glycoprotein (P-gp) expression in ENKTL.

Purpose of the Study:

  • To develop a novel HKDC1-based antitumor target for ENKTL.
  • To investigate the role of HKDC1 in ENKTL pathogenesis, including its involvement in EBV replication and P-gp expression.
  • To evaluate the therapeutic potential of a targeted peptide derived from HKDC1.

Main Methods:

  • HKDC1 expression levels were analyzed in ENKTL cells.
  • HKDC1 knockdown was performed to assess its impact on tumor growth.
  • A peptide (Tf-D-HKC8) targeting the C-terminal of HKDC1 was designed and synthesized.
  • The peptide's mechanism of action, including effects on mitochondrial function, EBV replication, and P-gp expression, was investigated.
  • In vivo efficacy was evaluated using ENKTL xenograft mouse models.

Main Results:

  • HKDC1 was significantly upregulated in ENKTL cells, and its knockdown suppressed tumor growth.
  • The Tf-D-HKC8 peptide inhibited the association of HKDC1 with VDAC1, leading to mitochondrial dysfunction and reactive oxygen species (ROS) overgeneration.
  • The peptide effectively suppressed EBV replication and P-gp expression in ENKTL cells.
  • Local injection of Tf-D-HKC8 peptide significantly inhibited tumor growth and EBV replication in vivo.

Conclusions:

  • HKDC1 is a critical target for ENKTL therapy.
  • The C-terminal peptide Tf-D-HKC8 demonstrates potent antitumor activity against ENKTL by modulating mitochondrial function and suppressing EBV.
  • HKDC1-based peptides represent a promising therapeutic approach for EBV-positive ENKTL.

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