PolG Inhibits Gastric Cancer Glycolysis and Viability by Suppressing PKM2 Phosphorylation

Abstract

Purpose

Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer-related death. There is a critical need for the development of novel therapies in GC. DNA polymerase gamma (PolG) has been implicated in mitochondrial homeostasis and affects the development of numerous types of cancer, however, its effects on GC and molecular mechanisms remain to be fully determined. The aim of the present research was to clarify the effects of PolG on GC and its possible molecular mechanism of action.

Methods

The GSE62254 dataset was used to predict the effect of PolG on prognostic value in GC patients. Lentivirus-mediated transduction was used to silence PolG expression. Western blot analysis evinced the silencing effect. Co-immunoprecipitation (Co-IP) analysis was performed to explore the potential molecular mechanism of action. Analysis of the glycolysis process in GC cells was also undertaken. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. Cell migration was detected using the Transwell device. Animal experiments were used to measure in vivo xenograft tumor growth.

Results

GC patients with low PolG expression have worse overall survival (OS) and progression-free survival (PFS). PolG binds to PKM2 and affects the activation of Tyr105-site phosphorylation, thus interfering with the glycolysis of GC cells. In vitro tumor formation experiments in mice also confirmed that PolG silencing of GC has a stronger proliferation ability. PolG can suppress GC cell growth both in vivo and in vitro.

Conclusion

Our study reveals a potential molecular mechanism between PolG and the energy metabolic process of GC tumor cells for the first time, suggesting PolG as an independent novel potential therapeutic target for tumor therapy, and providing new ideas for clinical GC treatment.

Keywords:

• DNA polymerase gamma
• energy metabolism
• tumor suppressor
• PKM protein
• stomach neoplasms

Abbreviation

GC, gastric cancer; PolG, DNA polymerase gamma; PKM2, pyruvate kinase M2; VEGF, vascular endothelial growth factor; ICIs, immune checkpoint inhibitors; KM, Kaplan–Meier method; OS, overall survival; PFS, progression-free survival; CCK-8, Cell Counting Kit-8.

Ethics Approval and Informed Consent

All animal experiments were approved by the Committee of China Medical University (IACUC Issue No. CMU2020166).

Consent for Publication

Written informed consent for publication was obtained from all participants.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or its revision and agreed to its submission to this journal; all authors gave their final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.