Glycolysis Inhibition of Autophagy Drives Malignancy in Ovarian Cancer: Exacerbation by IL-6 and Attenuation by Resveratrol.

peer reviewedCancer cells drive the glycolytic process towards the fermentation of pyruvate into lactate even in the presence of oxygen and functioning mitochondria, a phenomenon known as the "Warburg effect". Although not energetically efficient, glycolysis allows the cancer cell to synthesize the metabolites needed for cell duplication. Autophagy, a macromolecular degradation process, limits cell mass accumulation and opposes to cell proliferation as well as to cell migration. Cancer cells corrupt cancer-associated fibroblasts to release pro-inflammatory cytokines, which in turn promote glycolysis and support the metastatic dissemination of cancer cells. In mimicking in vitro this condition, we show that IL-6 promotes ovarian cancer cell migration only in the presence of glycolysis. The nutraceutical resveratrol (RV) counteracts glucose uptake and metabolism, reduces the production of reactive oxygen species consequent to excessive glycolysis, rescues the mitochondrial functional activity, and stimulates autophagy. Consistently, the lack of glucose as well as its metabolically inert analogue 2-deoxy-D-glucose (2-DG), which inhibits hexokinase 2 (HK2), trigger autophagy through mTOR inhibition, and prevents IL-6-induced cell migration. Of clinical relevance, bioinformatic analysis of The Cancer Genome Atlas dataset revealed that ovarian cancer patients bearing mutated TP53 with low expression of glycolytic markers and IL-6 receptor, together with markers of active autophagy, display a longer overall survival and are more responsive to platinum therapy. Taken together, our findings demonstrate that RV can counteract IL-6-promoted ovarian cancer progression by rescuing glycolysis-mediated inhibition of autophagy and support the view that targeting Warburg metabolism can be an effective strategy to limit the risk for cancer metastasis

Concomitant radiotherapy and paclitaxel for high-risk endometrial cancer: First feasibility study

Objective. Postoperative radiotherapy (RT) is the most used adjuvant treatment in high risk endometrial cancer (HREC), and it appears to reduce the incidence of pelvic relapses but doesn't seem to improve survival. Paclitaxel (P) has shown in vitro and clinical activity against endometrial cancer, and it is also a potent radiosensitizer by blocking dividing cells in G2/M phase. This is the first study that verifies the feasibility of a treatment with concomitant weekly chemotherapy and RT to potentially reduce the incidence of local and distant relapses in order to improve survival in HREC. Patients and Methods. Thirteen patients with HREC have entered the feasibility study at San Raphael Hospital University of Milan. All patients underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. Four patients presented stage IC disease, 2 women had IIB stage tumors, 5 patients revealed IIIA stage disease, and 2 had stage IIIC. The patients received P (60 mg./m2) via a continuous 1-h infusion once weekly during the 5 weeks of RT (mean radiation dose of 50.4 Gy). At the end of RT three additional consolidation courses of P (80 mg/m2) were subministered. Eleven patients received only pelvic irradiation; in 2 cases radiotherapy was performed on an extended field. Results. Eleven of the 13 enrolled patients have completed the radiochemotherapy regimen. A total of 100 courses of P were performed. All patients completed the RT. Adverse effects were evaluated. Hematological toxicity was mild: four cycles (4%) were delayed 1 week because of grade 1 neutropenia. No severe thrombocytopenia was identified. No hemotrasfusions were performed. One cycle was delayed for fever. Gastrointestinal adverse effects were observed in 2 patients, in which the cycles were delayed 1 week because of diarrhea. One cycle was delayed 1 week because of dermatitis. One patient developed a subocclusion 8 weeks after the end of the treatment, with medical resolution. No patients developed hypersensitivity reactions. Conclusions. Concomitant P and RT is safe and acceptable treatment in patients with HREC. Prospective clinical studies are necessary to evaluate the benefits of this regimen for the long-term survival rate

Cell-free Lactiplantibacillus plantarum OC01 supernatant suppresses IL-6-induced proliferation and invasion of human colorectal cancer cells: Effect on β-Catenin degradation and induction of autophagy

Background and aim: Gut microbiota is considered as a complex organ of human body. The interaction between the host and microbiota is dynamic and controlled by a huge number of factors, such as lifestyle, geography, pharmaceuticals, diet, and stress. The breakdown of this relationship could change microbiota composition favoring the onset of several diseases, including cancer. Metabolites released by microbiota bacterial strains have been reported to elicit protective effects on the mucosa that could contrast cancer development and progression. Here, we tested the ability of specific probiotic strain Lactiplantibacillus plantarum OC01-derived metabolites (NCIMB 30624) to contrast the malignant features of colorectal cancer (CRC) cells. Experimental procedure: The study was performed on two cell lines, HCT116 and HT29, cultured in 2D and 3D, and focused on the hallmarks of cell proliferation and migration. Results and conclusion: Probiotic metabolites reduced cell proliferation both in 2D and 3D-spheroid cultures, the latter model mimicking the growth in vivo. The bacterial metabolites also contrasted the pro-growth and pro-migratory activity of inteurleukin-6 (IL-6), an inflammatory cytokine abundantly found in the tumor microenvironment of CRC. These effects were associated with inhibition of the ERIC and of the mTOR/p70S6k pathways and with the inhibition of the E-to N-Cadherin switch. In a parallel study, we found that sodium butyrate (a representative of the main probiotic metabolites) induced autophagy and b-Catenin degradation, which is consistent with the growth inhibitory activity. The present data indicate that the metabolites of Lactiplantibacillus plantarum OC01 (NCIMB 30624) elicits anti-tumor effect and support its possible inclusion as adjuvant therapy of CRC for limiting cancer growth and progression. (c) 2023 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/)

Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of APC and β-Catenin Mutational Status

Colorectal cancer (CRC) pathogenesis is mainly driven by alterations in WNT signaling, which results in altered transcriptional activity of β-Catenin. Mutations in APC (Adenomatous Polyposis Coli) are reflected in β-Catenin hyperactivation and loss of proliferation control. Certain intestinal bacteria metabolites have shown the ability to limit CRC cell proliferation and CRC pathogenesis. Here, we investigated the molecular mechanism underlying the anti-proliferative activity of butyrate, a microbiota-derived short chain fatty acid, in two CRC cell lines, namely HCT116 and SW620, which bear a mutation in β-Catenin and APC, respectively. In particular, we focused on autophagy, a lysosome-dependent degradation pathway, which was shown to control intestinal tissue homeostasis. Butyrate reduced CRC cell proliferation, as witnessed by the downregulation of proliferation markers. TCGA bioinformatic transcriptomic analysis of CTNNB1 (β-Catenin) gene correlation in CRC patients showed that β-Catenin negatively correlates with the autophagy gene ATG4D. In CRC cells, regardless of the mutational state of APC or β-Catenin genes, butyrate caused the autophagy-mediated degradation of β-Catenin; thus, preventing its transcriptional activity. Autophagy gene silencing restored β-Catenin levels, allowing it to translocate into the nucleus to promote the expression of downstream genes associated with cancer cell proliferation. CRC-affected patients show driver mutations in the WNT pathway; thus, targeting its crucial effector may be a promising therapeutic strategy in CRC treatment; for instance, by using ad hoc probiotics that stimulate autophagy

High BECN1 Expression Negatively Correlates with BCL2 Expression and Predicts Better Prognosis in Diffuse Large B-Cell Lymphoma: Role of Autophagy

Diffuse large B-cell lymphoma (DLBCL) is characterized by high molecular and clinical heterogeneity. Autophagy, a lysosome-driven catabolic process devoted to macromolecular turnover, is fundamental in maintaining normal hematopoietic stem cells and progenitors homeostasis, and its dysregulation plays a critical role in the initiation and progression of hematological malignancies. One main regulator of autophagy is BECLIN-1, which may interact alternatively with either BCL-2, thus allowing apoptosis, or PI3KC3, thus promoting autophagy. The altered expression of BCL2 and BECN1 correlates with lymphoma outcomes, but whether this is associated with dysregulated cross-talk between autophagy and apoptosis remains to be elucidated. Analysis of the TCGA database revealed that BCL2 and BECN1 mRNA expression were inversely correlated in DLBCL patients. In representative DLBCL cell lines exposed to doxorubicin, the cells highly expressing BCL-2 were resistant, while the ones highly expressing BECLIN-1 were sensitive, and this correlated with low and high autophagy flux, respectively. Venetoclax targeting of BCL-2 increased while the spautin-1-mediated inhibition of BECLIN-1-dependent autophagy reversed doxorubicin sensitivity in the former and in the latter, respectively. By interrogating the TCGA DLBCL dataset, we found that BCL2 and BECN1 acted as negative and positive prognostic markers for DLBCL, respectively. The differentially expressed gene analysis in the respective cohorts revealed that BCL2 positively correlated with oncogenic pathways (e.g., glucose transport, HIF1A signaling, JAK-STAT signaling, PI3K-AKT-mTOR pathway) and negatively correlated with autophagy-related transcripts, while BECN1 showed the opposite trend. Notably, patients with high BECN1 expression displayed longer survival. Our data reveal, for the first time, that the modulation of BECLIN-1-dependent autophagy influences the prognosis of DLBCL patients and provide a mechanistic explanation supporting the therapeutic use of drugs that, by stimulating autophagy, can sensitize lymphoma cells to chemotherapy

Body composition changes in the first 6 months of life according to method of feeding

Background: Early feeding choices may affect long-term health outcomes. Therefore, understanding body composition changes in healthy breastfed infants has become an important research focus. Objectives: The aims of this review were to investigate the body composition changes that occur during weight loss in breastfed term newborns and to examine body composition differences between exclusively/predominantly breastfed and exclusively formula-fed infants in the first 6 months of life. Methods: We performed a review of the existing literature using PubMed. We searched for studies published in English since January 1, 2000, that involved human infants ranging in age from birth to 6 months. We used the following MEDLINE Medical Subject Headings: ((breastfeeding) OR (infant formula)) AND ((body composition) OR (bioelectrical impedance) OR (absorptiometry, photon) OR (total body potassium) OR (isotope dilution) OR (air-displacement plethysmography)). Our search yielded 6 studies. Results: Two studies reported that newborn weight loss was due to a reduction in the quantity of both fat mass and fat-free mass. Three out of 4 articles that evaluated body composition changes according to method of feeding reported no differences in body composition between exclusively/predominantly breastfed and exclusively formula-fed infants in the first 4.5 months of life. One study reported that exclusively breastfed infants at 3 months of age and exclusively breastfed boys at 6 months of age had higher fat mass contents compared to exclusively formula-fed infants. Conclusion: Because of the limited number of studies available, larger studies are needed to clarify the differences in body composition between exclusively/predominantly breastfed and exclusively formula-fed infants. \uc2\ua9 The Author(s) 2014

Resveratrol and Its Analogue 4,4'-Dihydroxy-trans-stilbene Inhibit Lewis Lung Carcinoma Growth In Vivo through Apoptosis, Autophagy and Modulation of the Tumour Microenvironment in a Murine Model

Lung cancer is the most prevalent cancer worldwide. Despite advances in surgery and immune-chemotherapy, the therapeutic outcome remains poor. In recent years, the anticancer properties of natural compounds, along with their low toxic side effects, have attracted the interest of researchers. Resveratrol (RSV) and many of its derivatives received particular attention for their beneficial bioactivity. Here we studied the activity of RSV and of its analogue 4,4'-dihydroxystilbene (DHS) in C57BL/6J mice bearing cancers resulting from Lung Lewis Carcinoma (LLC) cell implantation, considering tumour mass weight, angiogenesis, cell proliferation and death, autophagy, as well as characterization of their immune microenvironment, including infiltrating cancer-associated fibroblasts (CAFs). C57BL/6J mice started treatment with RSV or DHS, solubilised in drinking water, one week before LLC implantation, and continued for 21 days, at the end of which they were sacrificed, and the tumour masses collected. Histology was performed according to standard procedures; angiogenesis, cell proliferation and death, autophagy, infiltrating-immune cells, macrophages and fibroblasts were assessed by immunodetection assays. Both stilbenic compounds were able to contrast the tumour growth by increasing apoptosis and autophagy in LLC tumour masses. Additionally, they contrasted the tumour-permissive microenvironment by limiting the infiltration of tumour-associated immune-cells and, more importantly, by counteracting CAF maturation. Therefore, both stilbenes could be employed to synergise with conventional oncotherapies to limit the contribution of stromal cells in tumour growth

Implementation of Nutritional Strategies Decreases Postnatal Growth Restriction in Preterm Infants

Background: Prevention of postnatal growth restriction of very preterm infants still represents a challenge for neonatologists. As standard feeding regimens have proven to be inadequate. Improved feeding strategies are needed to promote growth. Aim of the present study was to evaluate whether a set of nutritional strategies could limit the postnatal growth restriction of a cohort of preterm infants. Methodology/Principal Findings: We performed a prospective non randomized interventional cohort study. Growth and body composition were assessed in 102 very low birth weight infants after the introduction of a set of nutritional practice changes. 69 very low birth weight infants who had received nutrition according to the standard nutritional feeding strategy served as a historical control group. Weight was assessed daily, length and head circumference weekly. Body composition at term corrected age was assessed using an air displacement plethysmography system. The cumulative parenteral energy and protein intakes during the first 7 days of life were higher in the intervention group than in the historical group (530\uc2\ub181 vs 300\uc2\ub193 kcal/kg, p<0.001 and 21\uc2\ub12.9 vs 15\uc2\ub13.2 g/kg, p<0.01). During weaning from parenteral nutrition, the intervention group received higher parental/enteral energy and protein intakes than the historical control group (1380\uc2\ub158 vs 1090\uc2\ub170 kcal/kg; 52.6\uc2\ub17 vs 42.3\uc2\ub110 g/kg, p<0.01). Enteral energy (kcal/kg/d) and protein (g/kg/d) intakes in the intervention group were higher than in the historical group (130\uc2\ub111 vs 100\uc2\ub113; 3.5\uc2\ub10.5 vs 2.2\uc2\ub10.6, p<0.01). The negative changes in z score from birth to discharge for weight and head circumference were significantly lower in the intervention group as compared to the historical group. No difference in fat mass percentage between the intervention and the historical groups was found. Conclusions: The optimization and the individualization of nutritional intervention promote postnatal growth of preterm infants without any effect on percentage of fat mass. \uc2\ua9 2012 Roggero et al

Growth z score changes from birth to discharge in AGA (*p = 0.008; **p = 0.003) and SGA infants (*p = 0.04; **p = 0.02).

<p>Growth z score changes from birth to discharge in AGA (*p = 0.008; **p = 0.003) and SGA infants (*p = 0.04; **p = 0.02).</p