Upregulation of the ALDOA/DNA-PK/p53 pathway by dietary restriction suppresses tumor growth

D Ma; X Chen; P-Y Zhang; H Zhang; L-J Wei; S Hu; J-Z Tang; M-T Zhou; C Xie; R Ou; Y Xu; K-F Tang

doi:10.1038/onc.2017.398

Upregulation of the ALDOA/DNA-PK/p53 pathway by dietary restriction suppresses tumor growth

Oncogene. 2018 Feb 22;37(8):1041-1048. doi: 10.1038/onc.2017.398. Epub 2017 Oct 30.

Authors

D Ma^{1

2}, X Chen^{1

2}, P-Y Zhang^{1

2}, H Zhang^{1

2}, L-J Wei^{1

2}, S Hu³, J-Z Tang⁴, M-T Zhou⁵, C Xie⁶, R Ou⁷, Y Xu², K-F Tang^{1

2}

Affiliations

¹ Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
² Institute of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
³ Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, People's Republic of China.
⁴ Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
⁵ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
⁶ Department of Radiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
⁷ Department of Gynaecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.

PMID: 29084207
DOI: 10.1038/onc.2017.398

Abstract

Dietary restriction (DR) delays the incidence and decreases the growth of various types of tumors; however, the mechanisms responsible for DR-mediated antitumor effects have not been unequivocally identified. Here, we report that DR suppresses xenograft tumor growth by upregulating a novel signaling pathway. DR led to upregulated aldolase A (ALDOA) expression in xenograft tumors. ALDOA physically interacted with the catalytic subunit of DNA-dependent protein kinase (DNA-PK) and promoted DNA-PK activation. Activated DNA-PK phosphorylated p53 and increased its activity. Although ALDOA can function as an oncogene in cultured cells, it can also activate the tumor suppressor p53. Thus, ALDOA overexpression in the presence of p53 suppressed xenograft tumor growth; however, when p53 was suppressed, ALDOA overexpression promoted xenograft tumor growth. Moreover, we demonstrated that p53 suppression inhibited the antitumor effects of DR. Our results indicate that upregulation of the ALDOA/DNA-PK/p53 pathway is a mechanism accounting for the antitumor effects of DR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Biomarkers, Tumor
Caloric Restriction
Carcinoma, Hepatocellular / etiology
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Carcinoma, Hepatocellular / prevention & control*
Cell Movement
Cell Proliferation
DNA-Activated Protein Kinase / genetics
DNA-Activated Protein Kinase / metabolism*
Diet / adverse effects*
Female
Fructose-Bisphosphate Aldolase / genetics
Fructose-Bisphosphate Aldolase / metabolism*
Gene Expression Regulation, Neoplastic*
Humans
Liver Neoplasms / etiology
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Liver Neoplasms / prevention & control*
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
Xenograft Model Antitumor Assays

Substances

Biomarkers, Tumor
Nuclear Proteins
TP53 protein, human
Tumor Suppressor Protein p53
DNA-Activated Protein Kinase
PRKDC protein, human
ALDOA protein, human
Fructose-Bisphosphate Aldolase