Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells



Austin, James A, Jenkins, Rosalind E, Austin, Gemma M, Glenn, Mark A, Dunn, Karen, Scott, Laura, Lucas, Claire M ORCID: 0000-0001-6674-7535 and Clark, Richard E ORCID: 0000-0002-1261-3299
(2019) Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells. BIOCHEMICAL JOURNAL, 476 (15). pp. 2255-2269.

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Abstract

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5' AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.

Item Type: Article
Uncontrolled Keywords: K562 Cells, Animals, Smegmamorpha, Humans, Neoplasms, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Neoplasm Proteins, Autoantigens, Signal Transduction, Oxidative Phosphorylation, AMP-Activated Protein Kinases, Autophagy-Related Protein-1 Homolog
Depositing User: Symplectic Admin
Date Deposited: 12 Aug 2019 14:16
Last Modified: 14 Oct 2023 09:30
DOI: 10.1042/BCJ20190121
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3051547