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Tumor Protein D52 (TPD52) Affects Cancer Cell Metabolism by Negatively Regulating AMPK
30 Pages Posted: 11 Jun 2019
More...Abstract
Background: The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. However, how this pathway is dysregulated in cancer remains unclear.
Methods: Using a tandem affinity purification/mass-spec technique and biochemical analyses, we identified Tumor protein D52 (TPD52) as an AMPKα-interacting molecule. To explore the biological effects of TPD52 in cancers, we conducted biochemical and metabolic assays in vitro and in vivo with cancer cells and TPD52 transgenic mice. Finally, we assessed the clinical significance of TPD52 expression in breast cancer patients using bioinformatics techniques.
Findings: We found that TPD52, initially identified to be overexpressed in many human cancers, forms a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. We generated TPD52 transgenic mice, and found that overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects in mice. Clinically, high TPD52 expression predicts poor survival of breast cancer patients.
Interpretation: The findings revealed that TPD52 is a novel regulator of energy stress-induced AMPK activation and cell metabolism. These results shed new light on AMPK regulation and understanding of the etiology of cancers with TPD52 overexpression.
Funding: This work was supported by the NCI grant CA196648 (to L.W. and Z.L.).
Declaration of Interest: All authors have no competing interests to declare, financial or otherwise.
Ethical Approval: These procedures were approved by the Institutional Animal Care and Use Committee (IACUC).
Keywords: AMP-activated protein kinase (AMPK), tumor protein D52 (TPD52), cell metabolism, breast cancer
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