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

Giusy Di Conza, Sarah Trusso Cafarello, Xingnan Zheng, Qing Zhang, Massimiliano Mazzone

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2836-2844
Number of pages9
JournalCell Reports
Volume18
Issue number12
DOIs
StatePublished - Mar 21 2017
Externally publishedYes

Fingerprint

Cell death
Starvation
Cell Death
Breast Neoplasms
Glucose
Apoptosis
Prolyl Hydroxylases
Degradation
Phosphoric Monoester Hydrolases
Heterografts
Proline
Nutrients
Tumors
Cells
Food
Substrates
Enzymes
Growth
Neoplasms
Proteins

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner. / Di Conza, Giusy; Trusso Cafarello, Sarah; Zheng, Xingnan; Zhang, Qing; Mazzone, Massimiliano.

In: Cell Reports, Vol. 18, No. 12, 21.03.2017, p. 2836-2844.

Research output: Contribution to journalArticle

Di Conza, Giusy ; Trusso Cafarello, Sarah ; Zheng, Xingnan ; Zhang, Qing ; Mazzone, Massimiliano. / PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner. In: Cell Reports. 2017 ; Vol. 18, No. 12. pp. 2836-2844.
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