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Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1

Ya-Nan Xue1, Bing-Bing Yu1, Jiu-Ling Li1

  • 1Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.

Experimental Cell Research
|December 12, 2018
PubMed

Insights

Zinc and p53 disrupt the mitochondrial binding of hexokinase 2 (HK2) in prostate cancer cells, inhibiting tumor growth. This discovery offers a novel therapeutic strategy targeting cancer cell metabolism and apoptosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Cell death regulators and metabolic enzymes interplay, offering insights into cancer therapy mechanisms.
  • Zinc and p53 induce apoptosis and regulate tumor cell metabolism, but the precise mechanisms are unclear.
  • Hexokinase 2 (HK2) possesses dual metabolic and apoptotic roles, making it a key target in cancer research.

Purpose of the Study:

  • To elucidate the mechanism by which zinc and p53 affect hexokinase 2 (HK2) function in prostate cancer.
  • To investigate the role of HK2's mitochondrial localization in prostate cancer cell apoptosis and metabolism.
  • To evaluate the therapeutic potential of targeting HK2 mitochondrial localization in prostate cancer.

Main Methods:

  • Analysis of zinc and p53 downstream targets in prostate cancer tissues and cell lines.
  • Investigation of HK2's subcellular localization, particularly its mitochondrial association.
  • Biochemical assays to determine the phosphorylation status of VDAC1 and its effect on HK2 binding.
  • Inhibition studies involving protein kinase B (Akt) and glycogen synthase kinase 3β (GSK3β).
  • Xenograft models to assess the in vivo efficacy of combined zinc and p53 treatment.

Main Results:

  • Hexokinase 2 (HK2) was identified as a downstream target of zinc and p53 in prostate cancer.
  • Mitochondrial localization of HK2 was found to be critical for its function.
  • Zinc and p53 were shown to disrupt HK2's mitochondrial binding by phosphorylating VDAC1, involving Akt inhibition and GSK3β activation.
  • Combined zinc and p53 treatment significantly inhibited tumor growth in a prostate cancer xenograft model.

Conclusions:

  • Zinc and p53 interfere with the mitochondrial localization of HK2 in prostate cancer cells.
  • This interference, mediated by VDAC1 phosphorylation, offers a novel mechanism for inducing apoptosis and inhibiting tumor metabolism.
  • Targeting HK2 mitochondrial localization presents a promising new therapeutic strategy for prostate cancer treatment.
Keywords:
AktGSK3βHK2VDACZincp53

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