Metformin induces distinct bioenergetic and metabolic profiles in sensitive versus resistant high grade serous ovarian cancer and normal fallopian tube secretory epithelial cells.

Metformin is a widely used agent for the treatment of diabetes and infertility, however, it has been found to have anti-cancer effects in a variety of malignancies including high grade serous ovarian cancer (HGSC). Studies describing the mechanisms by which metformin affects HGSC are ongoing, but detailed analysis of its effect on the cellular metabolism of both HGSC cells and their precursor, normal fallopian tube secretory epithelial cells (FTSECs), is lacking. We addressed the effects of metformin and the more potent biguanide, phenformin, on HGSC cell lines and normal immortalized FTSECs. Cell proliferation assays identified that FTSECs and a subset of HGSC cell lines are relatively resistant to the anti-proliferative effects of metformin. Bioenergetic and metabolomic analyses were used to metabolically differentiate the metformin-sensitive and metformin-resistant cell lines. Bioenergetically, biguanides elicited a significant decrease in mitochondrial respiration in all HGSC cells and FTSECs. However, biguanides had a greater effect on mitochondrial respiration in metformin sensitive cells. Metabolomic analysis revealed that metformin and phenformin generally induce similar changes in metabolic profiles. Biguanide treatment led to a significant increase in NADH in FTSECs and HGSC cells. Interestingly, biguanide treatment induced changes in the levels of mitochondrial shuttle metabolites, glycerol-3-phopshate (G3P) and aspartate, specifically in HGSC cell lines and not in FTSECs. Greater alterations in G3P or aspartate levels were also found in metformin sensitive cells relative to metformin resistant cells. These data identify bioenergetic and HGSC-specific metabolic effects that correlate with metformin sensitivity and novel metabolic avenues for possible therapeutic intervention

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why increased glucose metabolism is selected for in proliferating cells throughout nature.Burroughs Wellcome FundSmith Family FoundationStarr Cancer ConsortiumDamon Runyon Cancer Research Foundatio

Dynamic ROS Regulation by TIGAR: Balancing Anti-cancer and Pro-metastasis Effects

The role of ROS in cancer is complex, with studies demonstrating both pro- and anti-tumor effects. In a pancreatic ductal adenocarcinoma model, ROS limitation through TIGAR has been shown to initially support cancer development but to later become a metabolic liability in metastasizing cells that is counteracted by decreased TIGAR expression.status: publishe

Metabolism – A cornerstone of cancer initiation, progression, immune evasion and treatment response

Cancer is not a single disease, but a spectrum of diseases with common hallmarks. One of these hallmarks is deregulated metabolism. Changes in the metabolism of cancers are not a mere downstream event of an oncogenic transformation; rather, metabolism is an essential cornerstone enabling various aspects of cancer. In this review, we highlight the role of metabolism in cancer initiation, proliferation, metastasis formation, immune evasion, and therapy response. We further provide metabolic concepts by which metabolic pathways support these different aspects of cancer.status: publishe

Sialic Acid Metabolism: A Key Player in Breast Cancer Metastasis Revealed by Metabolomics

Metastatic breast cancer is currently incurable. It has recently emerged that different metabolic pathways support metastatic breast cancer. To further uncover metabolic pathways enabling breast cancer metastasis, we investigated metabolic differences in mouse tumors of differing metastatic propensities using mass spectrometry-based metabolomics. We found that sialic acid metabolism is upregulated in highly metastatic breast tumors. Knocking out a key gene in sialic acid metabolism, Cmas, inhibits synthesis of the activated form of sialic acid, cytidine monophosphate-sialic acid and decreases the formation of lung metastases in vivo. Thus, the sialic acid pathway may be a new target against metastatic breast cancer

Enhanced Lifetime of Cyanine Salts in Dilute Matrix Luminescent Solar Concentrators via Counterion Tuning

Organic luminophores offer great potential for energy harvesting and light emission due to tunable spectral properties, strong luminescence, high solubility, and excellent wavelength selectivity. To realize their full potential, the lifetimes of luminophores must extend to many years under illumination. Many organic luminophores, however, have a tendency to degrade and undergo rapid photobleaching, leading to the perception of intrinsic instability of organic molecules. In this work, we demonstrate that by exchanging the counterion of a heptamethine cyanine salt the photostability and corresponding lifetime of dilute cyanine salts can be enhanced by orders of magnitude from 10 h to an extrapolated lifetime of greater than 65,000 h under illumination. To help correlate and comprehend the underlying mechanism behind this phenomenon, the water contact angle and binding energy of each pairing were measured and calculated. We find that increased water contact angle, and therefore increasing hydrophobicity, generally correlates to improved lifetimes. Similarly, a lower absolute binding energy between cation and anion correlates to increased lifetimes. Utilizing the binding energy formalism, we predict the stability of a new anion and experimentally verify it with good consistency. Moving forward, these factors could be used to rapidly screen and identify highly photostable organic luminophore salt systems for a range of energy harvesting and light-emitting applications

Metformin induces distinct bioenergetic and metabolic profiles in sensitive versus resistant high grade serous ovarian cancer and normal fallopian tube secretory epithelial cells.

Metformin is a widely used agent for the treatment of diabetes and infertility, however, it has been found to have anti-cancer effects in a variety of malignancies including high grade serous ovarian cancer (HGSC). Studies describing the mechanisms by which metformin affects HGSC are ongoing, but detailed analysis of its effect on the cellular metabolism of both HGSC cells and their precursor, normal fallopian tube secretory epithelial cells (FTSECs), is lacking. We addressed the effects of metformin and the more potent biguanide, phenformin, on HGSC cell lines and normal immortalized FTSECs. Cell proliferation assays identified that FTSECs and a subset of HGSC cell lines are relatively resistant to the anti-proliferative effects of metformin. Bioenergetic and metabolomic analyses were used to metabolically differentiate the metformin-sensitive and metformin-resistant cell lines. Bioenergetically, biguanides elicited a significant decrease in mitochondrial respiration in all HGSC cells and FTSECs. However, biguanides had a greater effect on mitochondrial respiration in metformin sensitive cells. Metabolomic analysis revealed that metformin and phenformin generally induce similar changes in metabolic profiles. Biguanide treatment led to a significant increase in NADH in FTSECs and HGSC cells. Interestingly, biguanide treatment induced changes in the levels of mitochondrial shuttle metabolites, glycerol-3-phopshate (G3P) and aspartate, specifically in HGSC cell lines and not in FTSECs. Greater alterations in G3P or aspartate levels were also found in metformin sensitive cells relative to metformin resistant cells. These data identify bioenergetic and HGSC-specific metabolic effects that correlate with metformin sensitivity and novel metabolic avenues for possible therapeutic intervention