designed the study and wrote the manuscript; T.A.B. Nevertheless, the glycolytic reserve of the primary MM cells was limited and similar to that observed in the HMCLs. (A) Immunoblot analysis of HK2 and PKM2 expression in LME-1, MM1.S, and XG-3 Cas9-CTRL clones CTRL and FOXO KO clones (FOXO1 for LME-1, and FOXO3 for MM1.S and XG-3) treated overnight with 2.5 M MK2206 or left untreated. (B) Multivariate analysis of subgroups (n= 525) for OS. Gates open and registration begins at 6:30 p.m. By helping with projects such as the walk, Lavender is doing her part to help build momentum for UAMS as it prepares to apply for the NCI Designation from the National Cancer Institute. This was the pivotal moment when the AMA was no longer about the medicine and the physicians, it became America's most profitable LOBBY group. Similar to other cancer types, MM cells predominantly fulfill their energetic demands via glycolysis,2,3 a phenomenon known as the Warburg effect.4 In agreement, it was shown that the glycolysis rate-limiting enzyme, hexokinase II (HK2), is highly expressed in MM and is associated with poor prognosis.2,5,6. Contribution: T.A.B., G.d.W., and J.E.J.G. She says Lavender reminds her regularly to get screened, noting that colorectal cancer disproportionately affects the Black community. Kayla is a scion of the ubiquitous dynasty, which is one of America's most. Similarly, the normalized spare respiratory capacity of HMCLs was similar to that of other BCLs, demonstrating that HMCLs and BCLs do not differ with regard to mitochondrial adaptability.27 However, both HMCLs and Burkitt lymphoma cell lines (BLCLs) showed very limited normalized glycolytic reserve (Figure1A). performed analyses on clinical data and gene expression datasets; R.H.H. In addition, AKT kinase activity regulated mitochondrial respiration in MM (Figure2C, supplemental Figure2E-F). After Hillary Clinton's campaign ended before the 2008 Democratic Convention in Denver, Lavender went on a trip to Africa where the Clinton Foundation had several programs. At Christmas, she and her family, which included a younger sister and brother, would carol throughout the neighborhood. Within days of Harold's remarriage, Edith announced plans to marry Edward Krenn, a 28 year old Austrian architect. Of note, galactose is oxidized to pyruvate, yielding all glycolysis intermediates, thus indicating that it is unlikely that cell death is caused by the lack of glycolysis-derived metabolites required for anabolic processes.30. American Cancer Society - 1913 . These results confirm that FOXO suppresses the expression of genes involved in metabolic pathways in patients with MM (Figure3E). P-values were determined with Wald 2 test in Cox regression analysis. These effects appear to be cell/tissue contextspecific because several studies report the opposite, showing that FOXO expression is actually required for glucose metabolism and the TCA cycle in neural and intestinal stem cells.50,51 In agreement with our data, it was shown that FOXO3a antagonized MYC and repressed genes involved in the mitochondrial respiration in colon cancer cells52 and in glycolysis in melanoma cells.53. [11] She returned to America in 1921 after an eightyear stay. The oxidation of galactose to pyruvate by glycolysis yields no netATP, forcing cells to rely on mitochondrial respiration for ATPgeneration, which is characterized by an increased OCR (Figure1D).30,31 Galactose caused a significant decrease in the ECAR/OCR ratio in all HMCLs tested, indicating that HMCLs can switch to OXPHOS when forced to do so (Figure1E). [1] Edith helped fund the juvenile probation program of Chicago's pioneering Juvenile Court system when it was revealed that, although legislation set up the system, there was no provision to fund the probation officers. When no longer able to generate sufficient ATP from glycolysis, OXPHOS is increased, although not sufficiently to maintain a similar proliferation rate and viability. Mary Rockefeller, the wife of New York State Governor Nelson Rockefeller, sews the first of the new union labels onto a garment, January 15, 1959. Nonetheless, DCA increased the maximum respiration rate in MM cells, indicating an increased influx of pyruvate into the mitochondria and improved usage of mitochondrial respiration. -actin served as a loading control. A biographer of her father, however, makes it clear that this could not have been true: at the time of her son's death, Edith was with him at the family estate, Kykuit, at Pocantico Hills, New York. Interestingly, our findings could be extended to patients with MM and have important prognostic implications. She knew something was wrong, so she planned to drive to Texarkana to see a doctor her family knew. Cell lines, cell culture conditions, and details on reagents are provided in the supplemental Materials and Methods. Means SEM are shown (paired t test, n= 3-5 measurements). Notably, there was no correlation between 2-DG sensitivity and metabolic function in the cell lines tested (Figure1C and supplemental Figure1C), suggesting that 2-DGdependent cell death involves a different mechanism, such as the induction of endoplasmic reticulum stress through the inhibition of N-glycosylation, as previously described.28. "She is literally living proof that screening saves lives. She was quoted as saying, "I married King Tutankhamen when I was only sixteen years old. Mathilde and Max were married in London in April 1923. And she returned to working on campaigns when a friend ran for student body president. OCR decreased upon AKT inhibition in the presence of pyruvate as the sole carbon source, indicating that AKT directly regulates mitochondrial respiration. Edith was born on August 31, 1872 at her parents' home in Cleveland, Ohio. Her Texarkana doctor recommended that she go to UAMS in Little Rock for treatment. She was educated at home by private tutors and, unlike other women of means at the time, did not attend finishing school.[1]. UAMS started the walk in 2021 to honor patients with all forms of cancer and raise money for cancer research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. When evidence began to emerge that petroleum based medicine was causing cancer, Rockefeller founded the American Cancer Society, through which he suppressed that information. Lavender would spend 14 years at Alltel, moving up to a position where she worked on the development of Alltel's national wireless footprint with a partnership that put Alltel stores in Walmart stores across the nation. The first International Congress in Human Genetics to convene after WWII was held in Copenhagen in 1956. Furthermore, we demonstrated that AKT signaling is of crucial importance for glycolysis and mitochondrial respiration in MM cells. She joined Chi Omega sorority and was an Associated Student Government (ASG) representative. To further investigate the role of AKT signaling in the metabolic features of MM cells, HMCLs were treated with the allosteric AKT inhibitor MK2206. In accordance, despite their high rate of glycolysis, it was shown that MM cells also use OXPHOS because a combined treatment with the mitochondrial respiratory complex I inhibitor, metformin, and the glucose uptake inhibitor, ritonavir, synergized to induce death in MM cells.10 The rewiring of metabolic pathways and the flexibility to utilize different substrates are closely linked to recurrent genetic aberrations that characterize MM.11 In addition to fulfilling increased energy demands, several reports described changes in metabolism that lead to drug resistance in refractory MM.11,12 However, the key molecular factors that determine dynamic metabolic changes in MM cells have not been studied in detail. GSEA enrichment plots are shown, interrogating Reactome for glycolysis, KEGG for TCA cycle, and GSEA for Hallmark_oxidative_phosphorylation gene sets. Cell numbers and specific cell death were determined by 7-aminoactinomycin D staining (BioLegend, San Diego, CA) and calculated as published previously.18 Experimental details for the glucose uptake assay are provided in the supplemental Materials and Methods. Oftentimes, younger patients don't get timely diagnoses because doctors don't think they are old enough to have colorectal cancer, she says. "I was tired all of the time, but I was going nonstop, and I always have." For the glycolysis pathway, red, blue, and yellow symbols indicate >1.5-fold (FOXO-dependent) decrease in gene expression in LME-1, MM1.S, and XG-3, respectively. There, she had the strong family support she had known since childhood. "She just kept moving forward and kept educating people, and every time we have someone we know get cancer, Betsy's the first one there to guide them through that initial diagnosis.". AKT inhibition suppresses glycolysis and OXPHOS in MM cells. Furthermore, we show that MM cells perform glycolysis almost at their maximum rates and have a constrained metabolic adaptability. FOXO represses the expression of metabolic genes in MM cells. Guikema, Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; e-mail: j.e.guikema@amsterdamumc.nl. Moreover, our results suggest that AKT signaling sustains OXPHOS independently of its effects on glycolysis because AKT inhibition still decreased mitochondrial respiration when pyruvate was present as the sole carbon source, thereby obviating the need for pyruvate provided by glycolysis. Black Americans are about 20% more likely to get colorectal cancer and about 40% more likely to die from it than other ethnic groups. This is further substantiated by our GEP results showing that AKT inhibition resulted in the FOXO-dependent decreased expression of metabolic genes and gene sets. Laurance received many honors for his efforts on behalf of the environment and cancer research and treatment. "We got there, and it was snowing. Primary plasma cells from newly diagnosed patients with MM (n=2) and with a plasmacytosis of mononuclear cells being >80% were isolated as detailed in the supplemental Materials and Methods and as described previously.18 Primary MM cells were cultured overnight in supplemented Iscove modified Dulbecco medium with 10% fetal calf serum and 1 ng/mL interleukin-6 before experiments. As one of the wealthiest and most influential families in North America in the last 200 years, headed up by patriarch John D. Rockefeller I (pictured), the Rockefellers played an integral role in . In addition, regular screening can prevent colorectal cancer by allowing doctors to find and remove polyps before they turn into cancer. This notion, in combination with our finding that MM cells display limited metabolic adaptability suggests that the FOXO-dependent regulation of metabolic features may represent an attractive therapeutic Achilles heel. provided analytical support; J.D.S., T.C.A., and F.Z. In agreement, the glycolytic rate of primary MM cells was lower than that of HMCLs, perhaps explained by the low invitro proliferative capacity of primary cells. Replacing glucose with galactose resulted in a significant increase in cell death in several HMCLs (LME-1, XG-3, and RPMI-8226), suggesting that these cell lines are unable to generate sufficient ATP from OXPHOS, thus indicating defective mitochondrial respiration and limited metabolic adaptability. Rockefeller then took control of the American Medical Association and began offering grants to top medical schools under the mandate that only his approved curriculum be taught. This result is surprising because it was previously shown that a shorter (36 kDa) MCL-1 isoform is required for normal mitochondrial bioenergetics in mouse embryonic fibroblasts.54 However, it is unlikely that the overexpression of the shorter MCL-1 isoform would rescue mitochondrial respiration because we found many OXPHOS-associated genes decreased in a FOXO-dependent fashion upon AKT inhibition. The GraphPad Prism software package was used for statistical analyses (GraphPad Software, La Jolla, CA). Bar graphs (right panels) depict basal respiration values, and means SEM are shown (one-way ANOVA, with Bonferroni multiple comparison test, P< .0001, P< .001, P< .01, P< .05; ns= not significant. Flexner is considered the 'father' of modern medical education. From hectic politics to the unexpected peril of colorectal cancer, Lavender just laces up her shoes and deals with whatever life throws at her. [22], Harold McCormick and Edith Rockefeller, 1895, "MYSTERY OF CHICAGO'S 110 UNWED MILLION-HEIRESSES" Youngstown Vindicator, June 5, 1927, "MRS. M'CORMICK SAYS TUTANKHAMEN WED HER", The Hartford Courant, Mar 1, 1923. p. 22, "WOMEN TO UNITE TO DISPLAY RECORDS OF ACHIEVEMENT OF MODERN ENTERPRISE", Lawrence Daily Journal-World, Feb. 19, 1925 at p. 9, "MRS. McCORMICK'S CAREER. We raise nearly all of our money through private individual donations, which helps to . NONE OF FAMILY ON SHIP $50,000 Fee Reported for Psychoanalyst Who Will See Herto Chicago Home", "MRS. H. F. M'CORMICK OBTAINS DIVORCE IN FIFTY MINUTES; John D. Rockefeller's Daughter Gains Decree for Desertion, Which Husband Admits. Also, tours of the MammoVan, UAMS' mobile mammography unit, will be offered. Timon A. Bloedjes, Guus de Wilde, Gerarda H. Khan, Timothy C. Ashby, John D. Shaughnessy, Fenghuang Zhan, Riekelt H. Houtkooper, Richard J. Bende, Carel J. M. van Noesel, Marcel Spaargaren, Jeroen E. J. Guikema; AKT supports the metabolic fitness of multiple myeloma cells byrestricting FOXO activity. We have previously shown that prosurvival AKT signaling in MM critically depends on the inhibition of FOXO TFs, resulting in the stabilization of the antiapoptotic MCL-1 protein.18 Here, we show that the expression of key metabolic genes in MM is also regulated by AKT signaling that restrains FOXO-dependent gene repression. (A) Immunoblot analysis of HK2 and PKM2 in LME-1, MM1.S, and LP-1 HMCLs treated overnight with 2.5 M MK2206 AKT inhibitor or left untreated. She then went to UAMS, where she says the care she received saved her life. Means SEM of ECAR values are depicted (n= 5 measurements for each clone) and Seahorse XF injections are shown: glucose (=A), oligomycin (=B), 2-DG (=C). "It was a fabulous environment that day," Lavender says, noting that more than 1,000 people participated in 2022. ROCKEFELLER JR. GREETS DYING SISTER; Mrs. Edith McCormick Has Relapse in the Night, but Soon Rallies", "MRS. McCORMICK'S ESTATE; Once Estimated at $40,000,000 -- Great Losses Since Crash of 1929", Edith Rockefeller McCormick Trust records, https://en.wikipedia.org/w/index.php?title=Edith_Rockefeller_McCormick&oldid=1152097548, John Rockefeller McCormick (18971901), who died young from. "It was a wonderful experience being on the 'Hill,'" she says. In 1927, she was mentioned in a newspaper article about Chicago's wealthy unmarried, divorced, and widowed wealthy women. | 01 May 2023 02:14:13 . Moreover, we show that the FOXO-dependent repression of metabolic genes predicts superior overall survival (OS) in a large cohort of patients with MM. Groups were defined as high (red lines) or low (blue lines) expressing groups. She is especially interested in raising awareness of early onset colorectal cancer, which occurs in people under age 45 and is on the rise. ); and the Translational Research Institute (TRI) and grant KL2 TR003108 through the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (T.C.A.). She also studied astrology and reincarnation. Together, these results show that AKT crucially regulates the metabolic functioning of MM cells by controlling the activity of FOXO. In 2006, the campaign bug struck again when Lavender was invited to a local fundraiser for Hillary Clinton, who was running for re-election to the U.S. Senate. "I felt comfortable.". AKT was shown to regulate the expression of metabolic genes, primarily by controlling FOXO TFs.20,32 Previously, we defined a gene set that became repressed by FOXO upon AKT inhibition in MM cells (shared FOXOrepressed).18 GSEA indicated that the expression of these genes was enriched in MM cells (n= 75) in comparison with healthy donor plasma cells (n= 15),23 suggesting that FOXO is less active in MM cells (Figure3A). ", Copyright 2023, Northwest Arkansas Newspapers LLC. "It was the change and not knowing what was going to happen dealing with what was thrown at you and making the best way out of it.". Most genes involved in glycolysis and the TCA cycle significantly downregulated in a FOXO-dependent manner after AKT inhibition (Figure3C). During the race for ASG president, Lavender says, her friend's opponent had more money and used it to make professional yard signs. "I don't need her to convince me, but there could not be a better ambassador for UAMS. She attributes her good outcome to the doctors, especially her surgeon, Dr. Jason Mizell, and her oncologist, Dr. Sam Makhoul (now at CARTI), nurses and other staff who helped in her recovery. Mean values for basal glycolysis andnormalized glycolytic reserve (percentage of basal glycolysis) based on ECAR and mean values for basal respiration and normalized spare respiratory capacity(percentage of basal respiration) based on OCR are depicted (one-way ANOVA with Bonferroni multiple comparisons test; HMCLs vs BCLs, n= 5 measurements. (C) Seahorse XF mitochondrial stress test profiles of CTRL clones (left panels, n= 2), and FOXO KO clones (middle panels, n= 2) treated for 20 hours with 2.5 M MK2206 (blue lines) or left untreated (red lines). To further assess metabolic adaptability, HMCLs were cultured for 4 days in a medium in which glucose was replaced with galactose. Here, we show that human MM cell lines (HMCLs) rely on glycolysis for proliferation and survival. Moreover, the FOXO-dependent repression of glycolysis- and TCA-associated genes correlates with a favorable prognosis in a large cohort of patients with MM. They lived on the Arkansas side, which she calls the "good side" of Texarkana. SAID RICHES HURT CHILDREN Harold F. McCormick, Ex-Husband, Has Received $30,000 a Year Since Divorce. Seahorse extracellular flux (XF) metabolic profiling experiments were performed according to the manufacturers protocols. "[17] She was also said to be interested in astrology and to celebrate Christmas on December 15. April 30, 2023 at 7:30 a.m. Betsy Lavender at the Winthrop Rockefeller Cancer Institute at UAMS. "Sometimes, I think it was better than any drug they could have given me," she says. Its global headquarters is located in the American Cancer Society Center in Atlanta, Georgia. "The Rockefeller Women." Offsetting these medical advances, World War I killed 16.6 million people, including 6.8 million civilians. Numbers of patients at risk are tabulated below. Traveling was another favorite activity of the Lavender family, she says. Search for other works by this author on: Metabolic signature identifies novel targets for drug resistance in multiple myeloma, Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib, On respiratory impairment in cancer cells, An HK2 antisense oligonucleotide induces synthetic lethality in HK1-HK2+ multiple myeloma, Cyclin D1 targets hexokinase 2 to control aerobic glycolysis in myeloma cells, Metabolic heterogeneity in human lung tumors, The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type, Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin, Bortezomib resistance in multiple myeloma is associated with increased serine synthesis, Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells, The AKT kinase is activated in multiple myeloma tumor cells, Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma, The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses, PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells, Loss of PTEN expression leading to high Akt activation in human multiple myelomas, AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma, Is Akt the Warburg kinase?-Akt-energy metabolism interactions and oncogenesis, The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism, Analysis of PTEN deletions and mutations in multiple myeloma, Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3, Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling, Prognostic value of cyclin D2 mRNA expression in newly diagnosed multiple myeloma treated with high-dose chemotherapy and tandem autologous stem cell transplantations, Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation, Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles, Mitochondrial spare respiratory capacity: Mechanisms, regulation, and significance in non-transformed and cancer cells, Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation, Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells, Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants, Galactose enhances oxidative metabolism and reveals mitochondrial dysfunction in human primary muscle cells, The role of FOXO in the regulation of metabolism, Avalidated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1, TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3, Metabolic effects of recurrent genetic aberrations in multiple myeloma, Lactate dehydrogenase production and release in a newly established human myeloma cell line, Lactate, a putative survival factor for myeloma cells, is incorporated by myeloma cells through monocarboxylate transporters 1, Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer, Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines, Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited, Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements, Characterization of MYC translocations in multiple myeloma cell lines, Regulation of cancer cell metabolism: oncogenic MYC in the drivers seat, Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1, Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins, Akt stimulates aerobic glycolysis in cancer cells, Hexokinase-II positively regulates glucose starvation induced autophagy through TORC1 inhibition, The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes, Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis, FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells, Mitochondria define intestinal stem cell differentiation downstream of a FOXO/notch axis, FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression, FOXO3a-SIRT6 axis suppresses aerobic glycolysis in melanoma, Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration, 2023 by The American Society of Hematology. GEP data were obtained using samples from patients with MM who were at baseline and were undergoing total therapy 2 (TT2) or TT3 protocols.22 The clinical course for the patients showing high expression of these FOXO-repressed metabolic genes was characterized by a highly inferior OS (P< .0001). (B) Half maximal effective concentrations (EC50) of 2-DG for cell death in HMCLs and BCLs after 3 days of treatment. "Betsy Lavender has been such a tireless warrior and powerful voice about the importance of early detection for colon cancer," Couric says. OCR values from the Seahorse XF mitochondrial stress test are depicted, and means SEM are shown (t-test, n= 5-6 measurements).ttest,P< .05; MMPC, primary MM plasma cells. Harold Fowler McCormick Jr. (18981973), who married Anne Urquhart Brown "Fifi" (, Muriel McCormick (19031959), who married Elisha Dyer Hubbard (1878-1936), a nephew of. Please read our Terms of Use or contact us. Glycolysis, TCA cycle, and OXPHOS gene sets significantly depleted in MK2206-treated control clones in comparison with FOXO-deficient and untreated clones (Figure3B, supplemental Figure3A-C). In LME-1, FOXO1 was required, whereas in MM1.S and XG-3, FOXO3 was required, in line with our previous findings in these HMCLs.18 In addition, AKT inhibition almost completely abolished OXPHOS in the control clones, but not in the FOXO-deficient clones (Figure4C). On Saturday, Betsy Lavender will lead a team in the "Be a Part of the Cure Walk" hosted by the University of Arkansas for Medical Sciences' Winthrop P. Rockefeller Cancer Institute in Little Rock . Nonetheless, the aberrantly activated MYC-dependent gene expression is still subject to auxiliary regulation, in which PI3K/AKT signaling plays a pivotal role.44,45 However, the expression of MYC was significantly different in patients with MM classified as FOXO high (low AKT activity) vs those classified as FOXO low (high AKT activity) (supplemental Figure5).

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