"[18] Newspaper articles mention organizing troubles that caused it to be cancelled in 1929. Established in 1913, the foundation used the Rockefeller family wealth to ostensibly promote "public health" by funding mass vaccination campaigns and the founding of public health authorities around the world. (A) Seahorse XF real-time metabolic profiling of HMCLs (red symbols) and BCLs (blue, green, yellow, and light blue symbols), CpG-activated PBMNCs and purified human peripheral blood B cells (pink symbols). In 2016, Lavender caught the attention of Katie Couric, the former co-anchor of NBC's Today Show, who led a national colorectal cancer awareness campaign in the late 1990s after her husband, Jay Monahan, died from the disease at age 42. "Betsy Lavender has been such a tireless warrior and powerful voice about the importance of early detection for colon cancer," Couric says. In line with this, we showed that treatment with the purported glycolysis inhibitor 2-DG resulted in the variable induction of cell death in HMCLs and BCLs, which was not related to their glycolytic or respiratory capacity. She also helped local candidates campaign, putting up yard signs and other tasks. The overall conclusion here, and of our previous work,18 is that metabolism, proliferation, and survival of MM cells critically converge on the tumor-suppressive function of FOXO, which is actively restrained by AKT signaling. Editha McCormick (19031904), who also died young. During the race for ASG president, Lavender says, her friend's opponent had more money and used it to make professional yard signs. However, our results suggest that acetyl-CoA is not limiting for OXPHOS in MM cells because an increased acetyl-CoA formation caused by DCA treatment did not boost basal mitochondrial respiration. In MM, AKT activation is primarily caused by growth factors in the bone marrow and the sporadic loss of phosphatase and tensin homolog expression.17,21. These results suggest that AKT kinase activity exerts its oncogenic function in MM by driving glycolysis and the TCA cycle, which is associated with aggressive disease. This suggests that AKT is the pivotal kinase that crucially regulates both glycolysis and mitochondrial respiration in MM. Harold Fowler McCormick Jr. (18981973), who married Anne Urquhart Brown "Fifi" (, Muriel McCormick (19031959), who married Elisha Dyer Hubbard (1878-1936), a nephew of. CTRL, control; ES, enrichment score; FDR, false discovery rate; KEGG, Kyoto Encyclopedia of Genes and Genomes; KO, knockout; NES, normalized enrichment score. We developed a strategy to covalently tether drug fragments adjacent to allosteric sites in GPCRs to enhance . To further investigate the role of AKT signaling in the metabolic features of MM cells, HMCLs were treated with the allosteric AKT inhibitor MK2206. When evidence began to emerge that petroleum based medicine was causing cancer, Rockefeller founded the American Cancer Society, through which he suppressed that information. (A) Kaplan-Meier univariate analysis for the OS of k-means clusteringdefined groups of patients with MM (776 patients in total). 01 May 2023 02:14:13 . "It was coming here and feeling supported, and there wasn't a time that I have ever been scared.". [8] After extended analysis and intense study, Edith became a Jungian analyst, with a full-time practice of more than fifty patients. (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. The first International Congress in Human Genetics to convene after WWII was held in Copenhagen in 1956. The married couple spent their first two years living in Council Bluffs, Iowa, where Harold managed a branch of his father's business. "I was tired all of the time, but I was going nonstop, and I always have." I drive everybody crazy.". AKT signaling is an important driver of metabolism, either directly through the phosphorylation of key metabolic enzymes, or indirectly by controlling the expression of metabolic genes.20 The latter mainly involves the regulation of members of the FOXO TFs. All univariate P values were reported regardless of significance. In February 1923, she received some minor press for claiming to be the reincarnation of the wife of King Tutankhamen, whose tomb had just been explored and was a popular topic. In the summers, she says, they went swimming, set up Kool-Aid stands and played wiffleball. Our results demonstrate that the expression of several key metabolic genes involved in glycolysis, the tricarboxylic acid (TCA) cycle, and OXPHOS are repressed by FOXO TFs. 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. Edith and her father had an often stormy relationship, where her extravagance would often conflict with his frugality. 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. Similar effects of DCA treatment were observed in other cancer types, such as non-small cell lung cancer cells38 and breast cancer cells.39 Our results indicate that the reliance of MM cells on glycolysis for proliferation and survival is not related to an intrinsic inability to perform OXPHOS because MM cells are able to switch to OXPHOS when cultured in the presence of galactose instead of glucose. Here, we show that human MM cell lines (HMCLs) rely on glycolysis for proliferation and survival. Furthermore, we provide evidence that AKT sustains glycolysis and OXPHOS in MM by restricting FOXO. The increased reliance of cancer cells on glycolysis is often associated with decreased mitochondrial respiration, suggesting that aerobic glycolysis occurs at the expense of oxidative phosphorylation (OXPHOS).4 However, many tumors exhibit increased glycolysis and OXPHOS.7-9. OCR decreased upon AKT inhibition in the presence of pyruvate as the sole carbon source, indicating that AKT directly regulates mitochondrial respiration. 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. and G.d.W performed the experiments and analyses; R.J.B. Mean values of 3 individual experiments are depicted. Please read our Terms of Use or contact us. We raise nearly all of our money through private individual donations, which helps to . LE analysis provided the genes that contributed most prominently to the core enrichment of multiple gene sets associated with glycolysis, the TCA cycle, and OXPHOS (supplemental Table1). This year, she is already at work on raising money and recruiting a team of walkers for the third annual walk, which starts at 8:30 a.m. Saturday at War Memorial Stadium in Little Rock. As expected, ECAR decreased upon DCA treatment, confirming reduced lactate production, whereas basal respiration was generally not increased in HMCLs. Phosphorylation of AKT at Ser473, which marks its activation, slightly increased upon treatment with DCA in 2 out of 3 galactose-adapted HMCLs. In the summer after her junior year, she landed a coveted internship in Sen. Dale Bumpers' office in Washington. SAID RICHES HURT CHILDREN Harold F. McCormick, Ex-Husband, Has Received $30,000 a Year Since Divorce. Patients were clustered based on the FOXO-regulated LE gene sets; LE glycolysis, LE TCA cycle, or LE OXPHOS, which were derived by combining the LE genes from GSEAs performed for several glycolysis, TCA cycle, or OXPHOS gene sets (Supplemental Table1). performed analyses on clinical data and gene expression datasets; R.H.H. A heterogeneous response to 2-DG (half maximal effective concentrations [EC50s] ranging from 0.9 mM to >100 mM) was observed, which did not differ significantly between the BCL subtypes, although it is noteworthy that MM1.S (an HMCL) and Namalwa (a BLCL) showed a marked resistance (EC50 >100 mM) (Figure1B & supplemental Figure1B). 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. To explore whether these findings also apply to patients with MM, a large GEP dataset comprising 542 patients with MM was partitioned into 2 groups representing either high (n= 387) or low (n= 155) FOXO activity, based on the expression of the shared FOXOrepressed gene set.18 GSEA showed that patients with MM with low FOXO activity were significantly enriched (FDR <0.25) for glycolysis, TCA cycle, and OXPHOS-associated gene sets in comparison with those with high FOXO activity. Nevertheless, the glycolytic reserve of the primary MM cells was limited and similar to that observed in the HMCLs. Oftentimes, younger patients don't get timely diagnoses because doctors don't think they are old enough to have colorectal cancer, she says. The official, Dr . SPEEDING TO ILL SISTER; Financier, Despite Attack of Shingles, Is on Way to Chicago to See Mrs. Edith McCormick", "J.D. It all starts with John D. Rockefeller (1839 - 1937) who was an oil magnate, a robber baron, America's first billionaire, and a natural-born monopolist. 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. Kayla is a scion of the ubiquitous dynasty, which is one of America's most. She says Lavender reminds her regularly to get screened, noting that colorectal cancer disproportionately affects the Black community. She remained prominent after her divorce from McCormick and helped sponsor and organize several "Women's World Fairs" celebrating female achievement in the 1920s. To determine the metabolic adaptability, HMCLs were treated with dichloroacetate (DCA), which increases the activity of the pyruvate dehydrogenase complex and leads to to decreased production of lactate and increased decarboxylation of pyruvate to acetyl coenzyme A (acetyl-CoA), resulting in a shift of pyruvate toward mitochondrial metabolism.3,29 Phosphorylation of pyruvate dehydrogenase wasreduced upon DCA treatment, verifying on-target activity (supplemental Figure1D). It will be her second year to participate in the walk, and she hopes to raise even more money than she did last year, when her team took top fundraising honors in the individuals category. "We would go to different countries.". Original data are available on request from the corresponding author, Jeroen E. J. Guikema (j.e.guikema@amsterdamumc.nl). 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. These results confirm that FOXO suppresses the expression of genes involved in metabolic pathways in patients with MM (Figure3E). Offsetting these medical advances, World War I killed 16.6 million people, including 6.8 million civilians. I want a nation of workers." "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.". Associated Press text, photo, graphic, audio and/or video material shall not be published, broadcast, rewritten for broadcast or publication or redistributed directly or indirectly in any medium. As for cancer, oh yeah, the American Cancer Society was founded by none other than Rockefeller in 1913. Datasets from the HMCLs LME-1, MM1.S, and XG-3 were combined for GSEA. ; Her Leadership of Chicago Society Unchallenged to the End", "Fowler McCormick Dies at 74; ExChairman of Harvester", "MRS. MAX OSER DIES ON COAST; Granddaughter of the Late John D. Rockefeller, Sister of Fowfer McCormick ", "MRS. OSER GOES TO MOTHER; Rides in Twentieth Century to Bedside of Mrs. McCormick", "The Aryan Christ: The Secret Life of Carl Jung - ResearchGate", "A Quirky Visionary: Edith Rockefeller McCormick Reigned as Queen of Chicago's Elite", "MRS. H.F. M'CORMICK BACK AFTER 8 YEARS; Rockefeller's Daughter Denies Planning Divorce Action Against International Harvester Head. The American Cancer Society, Inc., is a 501 (c) (3) nonprofit corporation governed by a single Board of Directors that is responsible for setting policy, establishing long-term goals, monitoring general operations, and approving the organizational outcomes and allocation of resources. In 1925, she and other wealthy Chicago women including Miss Helen M. Bennett, Mrs. John V. Farwell, Mrs. Silas Strawn, Mrs. John Alden Carpenter, Mrs. B.F. Langworthy, Mrs. Florence Fifer Bohrer, and Mrs. Medill McCormick sponsored an international exposition to celebrate the progress and achievements of American women The first Woman's World's Fair, which was held at the American Exposition Palace on Lake Michigan in April 1925, and was held again each year in Chicago in April or May from 1926 to 1928. After being treated for depression by Jung, she became a successful Jungian psycho-analyst herself. Blood Adv 2023; 7 (9): 16971712. She called her parents to say she wanted to come home to Texarkana to see a doctor. Furthermore, AKT inhibition significantly decreased glycolysis, which required functional FOXO expression (Figure4B). Multiple myeloma (MM) plasma cells show increased glycolysis and oxidative phosphorylation (OXPHOS), which are characteristics associated with recurrent genetic aberrations that drive the proliferation and survival of MM cells. To continue their mission today, Shah says the RF must "directly confront climate change". 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. (E) OCR/ECAR ratios of HMCLs cultured for 4 days in a glucose-containing medium or in a galactose-containing, glucose-free medium. Among them are the Alfred P. Sloan, Jr. Memorial Award from the American Cancer Society (1969), the Medal of Freedom (1969), the Congressional Gold Medal (1991), and the Lady Bird Johnson Conservation Award for Lifetime Achievement (1997). When no longer able to generate sufficient ATP from glycolysis, OXPHOS is increased, although not sufficiently to maintain a similar proliferation rate and viability. She was educated at home by private tutors and, unlike other women of means at the time, did not attend finishing school.[1]. This indicates that in HMCLs and BLCLs, the glycolytic function is at its maximum and suggests that MM and BL are particularly reliant on glycolysis for proliferation and survival and have limited capacity to utilize glycolysis in response to increased energetic demands. She then traveled to Denver to work with media logistics for the Democratic National Convention. She also took on a new role to raise awareness of colorectal cancer and promote screening for the disease. She knew something was wrong, so she planned to drive to Texarkana to see a doctor her family knew. For the LE TCA and LE OXPHOS high groups (n= 178 and n= 170, respectively), the 5.5-year survival rate was 57% vs for the LE TCA and LE OXPHOS low groups, it was 71% (n= 598 and n= 606, respectively) (Figure5A). After arriving at her parents' home, she felt worse and went to the local hospital where she found out she had colorectal cancer. Lavender had early-onset colorectal cancer. Furthermore, we show that MM cells perform glycolysis almost at their maximum rates and have a constrained metabolic adaptability. 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. To determine the functional metabolic features of HMCLs in comparison with other mature malignant B-cell lines (BCLs), normal activated human peripheral blood mononuclear cells (PBMNCs), and activated purified B cells, glycolysis and mitochondrial stress tests were performed. Although novel treatment strategies have improved the prognosis and outcome of MM, most patients eventually relapse and become refractory to further treatment.1 Cancer cells are characterized by metabolic alterations, which are driven by oncogenes. Experimental details are provided in the supplemental Materials and Methods. In 1912, they hired prominent architect Charles A. Platt to build a mansion on their large country estate, located directly on Lake Michigan in Lake Forest, Illinois, which they named Villa Turicum, and which had extensive architecturally landscaped gardens. [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. For Lavender, 52, a colorectal cancer survivor, participating is part of her mission to encourage people to get screened for colorectal cancer. Lavender was 42 when she was diagnosed. Her father had surgery there, and the experience was good. To continue their mission today, Shah says the RF must "directly confront climate change". FOXO represses the expression of metabolic genes in MM cells. "I'm most grateful to have grown up in my family and in Texarkana," Lavender says. The role of FOXO downstream of AKT in MM cells was further substantiated by the FOXO-dependent decrease of HK2 protein expression and a modest decrease in PKM2 expression (Figure4A). After Barack Obama was elected president and Joe Biden became vice president, Lavender helped with inaugural festivities and then began coordinating travel arrangements for Biden and his family. John D. Rockefeller (1839-1937), founder of the Standard Oil Company, became one of the world's wealthiest men and a major philanthropist. And the fact that she's willing to scream it from the mountaintops makes me love her even more.". Black Americans are about 20% more likely to get colorectal cancer and about 40% more likely to die from it than other ethnic groups. Means SEM of OCR values are depicted (n= 5 measurements for each clone) and Seahorse XF injections are shown: oligomycin (=A), FCCP (=B), rotenone and antimycin A (=C). To further assess metabolic adaptability, HMCLs were cultured for 4 days in a medium in which glucose was replaced with galactose. For the TCA cycle a >1.2-fold (FOXO-dependent) decrease in gene expression is indicated.