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

Abstract

SummaryB55α 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.

RETRACTED ARTICLE: PHD2 acts as an oncogene through activation of Ras/Raf/MEK/ERK and JAK1/STAT3 pathways in human hepatocellular carcinoma cells

“…Initially, PHD2 has been considered to exert its role in carcinogenesis via HIF-dependent signalling [21]. However, recent paper illustrated that PHD2 also worked through HIFindependent pathways, like AKT/mTOR [17], PP2A/B55a [18], EGFR [22], NF-jB [23], and TGF-b1 [24]. The present paper illustrated Ras/Raf/MEK/ERK and JAK1/STAT3 as two novel signalling pathways that can be activated by PHD2 in the tumour cells.…”

“…Some researchers reported PHD2 as a tumour suppressor as its expression was able to suppress the initiation of melanoma [17]. Likewise, the silence of PHD2 would overcome apoptosis of breast cancer cells, which helped tumour cells against glucose starvation [18]. However, some researchers suggested the protumour functions of PHD2.…”

Prolyl Hydroxylase Domain-2 Protein Regulates Lipopolysaccharide-Induced Vascular Inflammation

“…PHD2 inhibition can block apoptosis of kidney epithelial cells and cancer cells through stabilizing HIF and regulatory B subunit of protein phosphatase 2 pathways. 46,47 It will be interesting to further determine their roles in PHD2regulated endothelial apoptotic responses and AJ integrity. HIF2a eKO mice, generated by the breeding of HIF-2a f/f and Tie2Cre þ/À mice, demonstrate aggravated LPS-induced death events and defective endothelial barrier integrity.…”

Beyond Computational Genomics towards Systems Metabolomics for Precision Oncology

“…Of course it is necessary to fully understand the metabolic and bioenergetic responses that are generated, only in cancer cells, by glucose deprivation. Figure 5B presents a concept map of the signaling pathways, centered on mitochondrial PP2A, which have been recently regarded to control glucose deprivation-induced cancer cell death (66,67). Glucose withdrawal causes rapid membrane depolarization and an influx of Ca 2+ , which activates a pathway given by kinase CAMK1 and demethylase PPME1.…”

“…The following activation of PP2A promotes cell death (66). Besides glucose starvation is followed by an increase of the α-ketoglutarate to fumarate ratio, which favour PHD2 activation that promotes cell death by degrading B55, the inhibitory subunit of PP2A (67). For other cancer cells, a glutamine starvation MYC-dependent apoptosis has been described (68).…”