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Cell Rep. 2017 Mar 21;18(12):2836-2844. doi: 10.1016/j.celrep.2017.02.081.

PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner.

Author information

1
Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium. Electronic address: giusy.diconza@unil.ch.
2
Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
3
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599, USA.
4
Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium. Electronic address: massimiliano.mazzone@vib-kuleuven.be.

Abstract

B55α is a regulatory subunit of the PP2A phosphatase. We have recently found that B55α-associated PP2A promotes partial deactivation of the HIF-prolyl-hydroxylase enzyme PHD2. Here, we show that, in turn, PHD2 triggers degradation of B55α by hydroxylating it at proline 319. In the context of glucose starvation, PHD2 reduces B55α protein levels, which correlates with MDA-MB231 and MCF7 breast cancer cell death. Under these conditions, PHD2 silencing rescues B55α degradation, overcoming apoptosis, whereas in SKBR3 breast cancer cells showing resistance to glucose starvation, B55α knockdown restores cell death and prevents neoplastic growth in vitro. Treatment of MDA-MB231-derived xenografts with the glucose competitor 2-deoxy-glucose leads to tumor regression in the presence of PHD2. Knockdown of PHD2 induces B55α accumulation and treatment resistance by preventing cell apoptosis. Overall, our data unravel B55α as a PHD2 substrate and highlight a role for PHD2-B55α in the response to nutrient deprivation.

KEYWORDS:

PHD2; PP2A; breast cancer; cell death; glucose starvation

PMID:
28329677
PMCID:
PMC5378984
DOI:
10.1016/j.celrep.2017.02.081
[Indexed for MEDLINE]
Free PMC Article

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