Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit 1,2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet 3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.Growth factor signalling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAP kinase) axes enhances oestrogen receptor activity and frequently underlies endocrine resistance in breast tumours 1,2,6 . Water-only fasting or plant-based diets that are simultaneously low in calories, sugar and protein and proportionally high in fat (fasting-mimicking diets (FMDs)) reduce circulating growth factors such as insulin and IGF1 2,6,7 . Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of oestrogen therapy (ET) and delay endocrine resistance.Low-serum, low-glucose cell culture conditions designed to mimic the effects of fasting or FMD (referred to as short-term starvation, STS) increased the anti-tumour activities of tamoxifen and fulvestrant in HR + /HER2breast cancer (BC) cell lines, and similar results were obtained in mouse xenografts of the same cell lines subjected to weekly cycles of fasting or FMD (Fig. 1a, Extended Data Figs. 1, 2a, b). STS also increased the anti-tumour activity of tamoxifen in tumour organoids from patients with HR + BC 8 , and weekly FMD cycles prevented acquired resistance to tamoxifen in mice (Extended Data Fig. 2c, d). Enhancement of ET activity through STS was dependent on the reduction in serum, but not glucose, as adding back glucose to the growth medium did not affect the observed potentiation (Extended Data Fig. 3a).In mice, besides increasing β-hydroxybutyrate levels (Extended Data Fig. 3b) and lowering blood glucose (from 6.3 ± 0.6 mmol l −1 to 4.1 ± 0....

In the last decade, substantial efforts have been made to identify NAD biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature. Both NAPRT and NAMPT increased intracellular NAD levels. NAPRT silencing reduced energy status, protein synthesis, and cell size in ovarian and pancreatic cancer cells. NAPRT silencing sensitized cells to NAMPT inhibitors both and; similar results were obtained with the NAPRT inhibitor 2-hydroxynicotinic acid. Reducing NAPRT levels in a BRCA2-deficient cancer cell line exacerbated DNA damage in response to chemotherapeutics. In conclusion, NAPRT-dependent NAD biosynthesis contributes to cell metabolism and to the DNA repair process in a subset of tumors. This knowledge could be used to increase the efficacy of NAMPT inhibitors and chemotherapy. .

Background: Mimivirus is highly glycosylated; however, nothing is known about its glycan composition and structure. Results: We identified a Mimivirus UDP-viosamine synthetic pathway, and we determined the sugar composition of viral fibers. Conclusion: Our data give further support to the presence of a Mimivirus-encoded glycosylation machinery. Significance: These results contribute to shed light on the origin of viral glycosylation systems.

The major capsid protein Vp54 from the prototype chlorovirus Paramecium bursaria chlorella virus 1 (PBCV-1) contains four Asnlinked glycans. The structure of the four N-linked oligosaccharides and the type of substitution at each glycosylation site was determined by chemical, spectroscopic, and spectrometric analyses. Vp54 glycosylation is unusual in many ways, including: (i) unlike most viruses, PBCV-1 encodes most, if not all, of the machinery to glycosylate its major capsid protein; (ii) the glycans are attached to the protein by a β-glucose linkage; (iii) the Asn-linked glycans are not located in a typical N-X-(T/S) consensus site; and (iv) the process probably occurs in the cytoplasm. The four glycoforms share a common core structure, and the differences are related to the nonstoichiometric presence of two monosaccharides. The most abundant glycoform consists of nine neutral monosaccharide residues, organized in a highly branched fashion. Among the most distinctive features of the glycoforms are (i) a dimethylated rhamnose as the capping residue of the main chain, (ii) a hyperbranched fucose unit, and (iii) two rhamnose residues with opposite absolute configurations. These glycoforms differ from what has been reported so far in the three domains of life. Considering that chloroviruses and other members of the family Phycodnaviridae may have a long evolutionary history, we suggest that the chlorovirus glycosylation pathway is ancient, possibly existing before the development of the endoplasmic reticulum and Golgi pathway, and involves still unexplored mechanisms.virus-encoded glycosylation | glucose/asparagine linkage | cytoplasmic glycosylation | glycopeptide | glycobiology