RETRACTED: PHGDH Expression Is Required for Mitochondrial Redox Homeostasis, Breast Cancer Stem Cell Maintenance, and Lung Metastasis

Abstract

Intratumoral hypoxia stimulates enrichment of breast cancer stem cells (BCSC), which are critical for metastasis and patient mortality. Here we report a metabolic adaptation that is required for hypoxia-induced BCSC enrichment and metastasis. Hypoxiainducible factors coordinately regulate expression of genes encoding phosphoglycerate dehydrogenase (PHGDH) and five downstream enzymes in the serine synthesis pathway and mitochondrial one-carbon (folate) cycle. RNAi-mediated silencing of PHGDH expression in both estrogen receptor-positive and negative breast cancer cells led to decreased NADPH levels, disturbed mitochondrial redox homeostasis, and increased apoptosis, which abrogated BCSC enrichment under hypoxic conditions. PHGDH-deficient cells exhibited increased oxidant levels and apoptosis, as well as loss of BCSC enrichment, in response to treatment with carboplatin or doxorubicin. PHGDH-deficient cells were relatively weakly tumorigenic and tumors that did form were deficient in BCSCs, abolishing metastatic capacity. Our findings highlight a role for PHGDH in the formation of secondary (recurrent or metastatic) tumors, with potential implications for therapeutic targeting of advanced cancers. Cancer Res; 76(15); 4430-42. Ó2016 AACR.

Escaping Death: Mitochondrial Redox Homeostasis in Cancer Cells

“…In breast cancer cells, PHGDH knockdown and consequent impairment of the mitochondrial folate cycle led to a decrease in NADPH level of ~50 and ~30% in MDA-MB-231 and in MCF7 cell lines, respectively (107), thus confirming the prediction by Fan and colleagues. Interestingly, exposure of breast cancer cell lines to hypoxia led to a repressed expression of G6PD, while increasing the expression of genes involved in serine synthesis pathway and mitochondrial folate cycle (107). These data suggest that HIF-1α is involved in the switch from cytosolic to mitochondrial NADPH production by upregulating the mitochondrial folate cycle.…”

“…Hypoxia upregulates PHGDH, PSAT1, PSPH, SHMT2, MTHFD2, and MTHFD1L, thus protecting breast cancer stem cells from oxidative damage (107). Consistent with this notion, PHGDH knockdown abrogates breast cancer stem cell survival under hypoxia, without impairing cancer cell proliferation, and increases oxygen consumption rate and extracellular acidification rate as a consequence of reduced glucose shunting to the serine synthesis pathway.…”

Targeting Metabolism for Cancer Therapy

“…More recently, it was found that increased expression of the serine synthesis enzyme phosphoglycerate dehydrogenase (PHGDH) in some cancers can result from copy number gain of a region on chromosome 1p (Beroukhim et al, 2010; Locasale et al, 2011; Possemato et al, 2011) or a consequence of oncogenic signaling, including NRF2 and ATF4 signaling (DeNicola et al, 2015), or hypoxia responses (Samanta et al, 2016). The PHGDH gene encodes the enzyme that catalyzes conversion of the glycolytic intermediate 3-phosphoglycerate into 3-phosphohydroxypyruvate, and 3-phosphohydroxypyruvate is converted to serine via two subsequent reactions (Figure 6).…”

Maintenance of redox homeostasis by hypoxia-inducible factors

“…In breast cancer cells, analysis of gene expression revealed that, irrespective of the estrogen receptor (ER) status, hypoxia induced the expression of the three enzymes of the SSP (PHGDH, PSAT1 and PSPH) and three enzymes required for mitochondrial 1CM (SHMT2, MTHFD2, and MTHFD1L) in a HIF-dependent manner [34]. In contrast, the enzymes required for cytosolic 1CM (SHMT1, MTHFD1) were not hypoxia-induced in most breast cancer cell lines.…”