The Hexosamine Biosynthetic Pathway leads to elevated post-translation addition of O-linked-βN-acetylglucosamine (O-GlcNAc) on intracellular proteins. Cancer cells elevate total O-GlcNAcylation by increasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation in cancer cells inhibits oncogenesis. Here, we demonstrate that O-GlcNAcylation regulates glycolysis in cancer cells via HIF-1α and its transcriptional target GLUT1. Reducing O-GlcNAcylation increases α-ketoglutarate, HIF-1 hydroxylation and interaction with VHL resulting in HIF-1α degradation. Reducing O-GlcNAcylation in cancer cells results in activation of ER stress and apoptosis of cancer cells mediated through CHOP induction of BCL2-family proteins. HIF-1α and GLUT1 are critical for OGT-mediated regulation of metabolic stress as overexpression of stable HIF-1 or GLUT1 rescues metabolic defects and apoptosis. Human basal-like breast cancers with high levels of HIF-1α contain elevated OGT, O-GlcNAcylation and lower OGA levels correlate independently with poor patient outcome. Thus, O-GlcNAcylation regulates cancer cell metabolic reprograming and survival stress signaling via regulation of HIF-1α.
Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treatment of postmenopausal women, and men, with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–), PIK3CA-mutated, advanced breast cancer (ABC). Hyperglycemia is a common, on-target adverse effect that impairs treatment efficacy and increases the rate of treatment delays, dose reductions, and discontinuation. Currently, there are no clear guidelines on how to manage hyperglycemia due to alpelisib when metformin is not effective. In this case series, we review 3 subjects with ABC that developed hyperglycemia during alpelisib-fulvestrant therapy and were successfully managed with dietary and pharmacologic interventions. These cases provide anecdotal evidence to support the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and very low carbohydrate diets to minimize hyperglycemia during alpelisib therapy.
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease affecting at least a quarter of the world’s population. NAFLD is commonly associated with other metabolic conditions such as insulin resistance, type 2 diabetes, obesity, and dyslipidemia. Given the liver’s prominent role in regulating glucose and lipid homeostasis, we hypothesized that subjects with NAFLD have a distinct profile of blood analytes. This investigation examines the association between NAFLD and circulating markers of glucose and lipid metabolism in order to identify a NAFLD-specific metabolite panel that can be used as a predictive biomarker in future studies. We are performing a cross-sectional study in 500 subjects to identify genetic and hormonal factors that correlate with the presence of NAFLD. This abstract reports a preliminary analysis of the results from the first 45 subjects enrolled. Fasting blood samples were collected from 31 subjects with NAFLD and 14 subjects with other metabolic diseases (‘Other’) and without radiologic evidence of NAFLD. The following analytes were measured: serum alanine aminotransferase (ALT), total cholesterol, direct-LDL, HDL, triglycerides, ApoB, small dense LDL-C (sdLDL), VLDL, Lp(a), cholesterol absorption/production markers (beta-sitosterol, campesterol, lathosterol, and desmosterol), glucose, insulin, hemoglobin A1C, adiponectin, hs-CRP, and fatty acids (saturated and unsaturated). Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin levels, and fatty acids were batched together by structural similarity and reported as indices. The groups were compared using multiple t-tests or the Kolmogorov-Smirnov test when data were non-parametric. The NAFLD group had a mean age 48.4 ± 12.9 yrs and BMI 32.9 ± 6.6 kg/m2. These participants were 61% female and 58% had dyslipidemia, 25% pre-diabetes, and 25% type 2 diabetes. The Other group had a mean age 49.9 ± 12.9 yrs and BMI 39.1 ± 15.6 kg/m2. They were 64% female and 57% had dyslipidemia, 14% pre-diabetes, and 21% type 2 diabetes. ALT was higher in the NAFLD group (55 ± 40 vs 27 ± 22 IU/L, P<0.001). Intriguingly, the saturated fatty acid index was elevated in the NAFLD group (32.5 ± 1.9 vs 30.1 ± 2.2 %, P<0.05), and the omega-6 fatty acid index was elevated in the Other group (42.9 ± 3.7 vs 38.5 ± 4.7 %, P<0.05). These changes led to an unsaturated/saturated fatty acid ratio that was significantly lower in the NAFLD group (2.0 ± 0.1 vs 2.3 ± 0.2, P<0.01). There were no other significant differences in the blood metabolites and hormones. In this small sample comparing subjects with metabolic disease with and without NAFLD, levels of ALT and the ratio of circulating unsaturated/saturated fatty acids are distinguishing features of NAFLD. These may be helpful measures to identify subjects with metabolic disease that require further evaluation for NAFLD.
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