Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism

Metformin inhibits cancer cell proliferation, and epidemiology studies suggest an association with increased survival in patients with cancer taking metformin; however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation, whereas increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer.German Science Foundation (Grant FE1185)National Institutes of Health (U.S.)Glenn Foundation for Medical ResearchNational Institutes of Health (U.S.) (Grant 5-P50-090381-09)National Institutes of Health (U.S.) (Grant 5-P30-CA14051-39)Burroughs Wellcome FundSmith Family FoundationDamon Runyon Cancer Research FoundationNational Institutes of Health (U.S.) (Grant 1R01DK075850-01)National Institutes of Health (U.S.) (Grant 1R01CA160458-01A1

The Tumor Suppressive Role of eIF3f and Its Function in Translation Inhibition and rRNA Degradation

Deregulated translation plays an important role in human cancer. We previously reported decreased eukaryotic initiation factor 3 subunit f (eIF3f) expression in pancreatic cancer. Whether decreased eIF3f expression can transform normal epithelial cells is not known. In our current study, we found evidence that stable knockdown of eIF3f in normal human pancreatic ductal epithelial cells increased cell size, nuclear pleomorphism, cytokinesis defects, cell proliferation, clonogenicity, apoptotic resistance, migration, and formation of 3-dimensional irregular masses. Our findings support the tumor suppressive role of eIF3f in pancreatic cancer. Mechanistically, we found that eIF3f inhibited both cap-dependent and cap-independent translation. An increase in the ribosomal RNA (rRNA) level was suggested to promote the generation of cancer. The regulatory mechanism of rRNA degradation in mammals is not well understood. We demonstrated here that eIF3f promotes rRNA degradation through direct interaction with heterogeneous nuclear ribonucleoprotein (hnRNP) K. We showed that hnRNP K is required for maintaining rRNA stability: under stress conditions, eIF3f dissociates hnRNP K from rRNA, thereby preventing it from protecting rRNA from degradation. We also demonstrated that rRNA degradation occurred in non-P body, non-stress granule cytoplasmic foci that contain eIF3f. Our findings established a new mechanism of rRNA decay regulation mediated by hnRNP K/eIF3f and suggest that the tumor suppressive function of eIF3f may link to impaired rRNA degradation and translation

The Translation Initiation Factor 3f (eIF3f) Exhibits a Deubiquitinase Activity Regulating Notch Activation

The translation initiation factor complex eIF3f has an intrinsic deubiquitinase activity and regulates the Notch signaling pathway

Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation

Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses

MYC regulation of glutamine--proline regulatory axis is key in luminal B breast cancer

Background: Altered cellular metabolism is a hallmark of cancer and some are reliant on glutamine for sustained proliferation and survival. We hypothesise that the glutamine–proline regulatory axis has a key role in breast cancer (BC) in the highly proliferative classes. Methods: Glutaminase (GLS), pyrroline-5-carboxylate synthetase (ALDH18A1), and pyrroline-5-carboxylate reductase 1 (PYCR1) were assessed at DNA/mRNA/protein levels in large, well-characterised cohorts. Results: Gain of PYCR1 copy number and high PYCR1 mRNA was associated with Luminal B tumours. High ALDH18A1 and high GLS protein expression was observed in the oestrogen receptor (ER)+/human epidermal growth factor receptor (HER2)– high proliferation class (Luminal B) compared with ER+/HER2– low proliferation class (Luminal A) (P=0.030 and P=0.022 respectively), however this was not observed with mRNA. Cluster analysis of the glutamine–proline regulatory axis genes revealed significant associations with molecular subtypes of BC and patient outcome independent of standard clinicopathological parameters (P=0.012). High protein expression of the glutamine–proline enzymes were all associated with high MYC protein in Luminal B tumours only (P<0.001). Conclusions: We provide comprehensive clinical data indicating that the glutamine–proline regulatory axis plays an important role in the aggressive subclass of luminal BC and is therefore a potential therapeutic target

O-308 The impact of NOSE colectomy and laparoscopic conventional segmental resection on bowel function and quality of life among patients with rectal endometriosis: prospective randomized trial

Abstract Study question What is the impact of laparoscopic conventional or NOSE colorectal resection on bowel function in patients with deep endometriosis infiltrating the rectum one year postoperatively? Summary answer Both conventional and NOSE colectomy improved the functional outcomes and quality of life among patients with deeply invasive rectal endometriosis one year after bowel surgery. What is known already Conventional laparoscopic approach to the surgical management of deep endometriosis infiltrating the rectum appears to assure improved digestive functional outcomes. NOSE technique for colorectal disease can significantly reduce the duration of hospital stay, accelerate postoperative recovery with better cosmetic results, and in particular, result in less postoperative pain and fewer complications. However, long-term solid data about gastrointestinal well-being after segmental bowel or NOSE resection for deep endometriosis are still missing. Study design, size, duration Between the 1st September 2019 - 31th of December 2020 we performed a 2-arm unblinded prospective randomized trial, enroling 91 patients with deep infiltrating rectal endometriosis up to 15 cm from the anal verge. Patients aged between 18 and 45 years, with deep endometriosis infiltrating at least the muscular layer in depth, and up to 50% of rectal circumference, complaining pain, bowel symptoms and/or infertility were included. The average follow up time was 14±2.6 months. Participants/materials, setting, methods Patients were enroled at Semmelweis University, Department of Obstetrics and Gynecology, Budapest, Hungary and had either conventional laparoscopic bowel resection or NOSE resection. Randomization was performed preoperatively using the simple randomization method. The primary endpoint was to assess the bowel function and quality of life by using the Endometriosis Health Profile 30, the Gastrointestinal Quality of Life Index and the Low Anterior Resection Syndrome score preoperatively, 1 month, 6 months, 1 year after the surgery. Main results and the role of chance A total of 91 patients were enroled. 39 patients were in the NOSE surgery arm, 49 were in the Conventional laparoscopic surgery arm. One patient was lost to follow-up and we had two cases of drop out from the trial after randomization due to performing non intended disc resection. This cases were excluded from the study. There was no conversion to laparotomy.The overall scores on Gastrointestinal Quality of Life Index (GIQLI), Low Anterior Resection Syndrome scores (LARS) and Endometriosis Health Profile 30 (EHP30) scores did not reveal significant differences between the two groups. LARS scores were improved, but did not reveal significant differences 12 months (T3) after the operation compared with the preoperative (T0) values in both groups (Conventional surgery group: T0=21.41 T3= 17.90; p = 0.934, NOSE surgery goup T0= 26.53 T3= 18.23; p = 0.229). GIQLI scores were significantly improved 12 months after the operation compared with the baseline values in Conventional surgery group T0= 95.44 T3= 111.39 p = 0.002. EHP30 scores were significantly improved concerning pain, emotion well-being, control and powerlessness, self-image, social support and sexuality scale 12 months after the operation compared with the preoperative values in both groups. Limitations, reasons for caution An obvious bias of performance is the lack of blinding, however blinding was not feasible due to the clinical nature of our study. We report no imprecision in patient selection, but a potential source of attrition bias in our data occured in a total number of three cases in NOSE-group. Wider implications of the findings Our study does not show a statistically significant difference between conventional or NOSE surgery for short and mid-term functional digestive outcomes. Occurrence of longterm bowel dysfunction does not appear to be related to a specific surgical technique. Trial registration number ClinicalTrials.gov number: NCT04109378 </jats:sec