He was also a "big, big" Razorback fan, she says, a passion she shares with him. In addition, we show that the LE glycolysis, LE TCA, and LE OXPHOS gene sets are significantly enriched in MMPCs from newly diagnosed patients (Figure5B) and patients with refractory/relapsed MM in comparison with those having healthy donor plasma cells, but not in those with monoclonal gammopathy of undetermined significance. Metabolic alterations are important cancer-associated features that allow cancer cell transformation and survival under stress conditions. supervised the study; and all authors read and approved the final manuscript. 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. ; 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. Enrichment plots for Reactome glycolysis, KEGG TCA cycle, and GSEA Hallmark_oxidative_phosphorylation gene sets are shown. And she returned to working on campaigns when a friend ran for student body president. Lavender had early-onset colorectal cancer. The effects of AKT inhibition on the OCRs were similar in MCL-1 overexpressing MM cells and the control cells, indicating that survival and mitochondrial respiration are independently regulated by AKT (supplemental Figure2H). For Lavender, staying positive is key to dealing with cancer and all of life's challenges. | I had sat in it many times. "She is literally living proof that screening saves lives. EDITH ROCKEFELLER TO GET $8,419,032", "J.D. (B) GSEA in Cas9-CTRL HMCL clones treated overnight with 2.5 M MK2206 (CTRL+MK) vs the combination of untreated CTRL clones and FOXO KO clones, either treated overnight with 2.5 M MK2206 or left untreated (REST). Contribution: T.A.B., G.d.W., and J.E.J.G. Her mother would play piano and they would all sing. Moreover, the FOXO-dependent repression of glycolysis- and TCA-associated genes correlates with a favorable prognosis in a large cohort of patients with MM. Previous works by us and others have shown that AKT plays a pivotal role in the survival and growth of MM cells.13-18 We recently showed that AKT restrains the tumor-suppressive functions of forkhead box O (FOXO) transcription factors (TFs) in MM.18 Importantly, AKT is a central node in the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin pathway that connects proliferation, survival, and cellular metabolism and drives glycolysis.19,20 Activation of AKT is common in cancer, either by activating mutations or by growth factors provided by the tumor microenvironment. [13] He was given custody of their youngest daughter Mathilde so that she could marry Max Oser, a Swiss riding instructor. "It was coming here and feeling supported, and there wasn't a time that I have ever been scared.". Edith and her father had an often stormy relationship, where her extravagance would often conflict with his frugality. Patient material was obtained according to the ethical standards of our institutional medical ethical committee, as well as in agreement with the 1975 declaration of Helsinki, as revised in1983. "We got there, and it was snowing. "UAMS is Arkansas' cancer center," Lavender says, adding that she encourages Arkansans with cancer to consider UAMS for treatment. 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. Only the other day, while glancing through an illustrated paper, I saw a picture of a chair removed from the King's chamber. Lavender's experience would be positive as well. ); 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.). [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. 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. "Sometimes, I think it was better than any drug they could have given me," she says. These results confirm that FOXO suppresses the expression of genes involved in metabolic pathways in patients with MM (Figure3E). Classification of patients with MM according to several metabolism-associated gene sets revealed that the FOXO-dependent repression of these genes confers a favorable prognosis. After being treated for depression by Jung, she became a successful Jungian psycho-analyst herself. As for cancer, the American Cancer Society was founded by Rockefeller himself in 1913. "So during Colon Cancer Month [March], I'm a beast about promoting screenings. 1 Cancer cells are characterized by metabolic alterations, which are driven by oncogenes. She and her husband Harold Fowler McCormick were prominent in Chicago society, supporting many causes, including the citys first opera company. Most genes involved in glycolysis and the TCA cycle significantly downregulated in a FOXO-dependent manner after AKT inhibition (Figure3C). 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. Bair, Deirdre, "Jung - A Biography" London: Time-Warner Books UK, 2004, This page was last edited on 28 April 2023, at 05:29. -actin served as a loading control. (A) Kaplan-Meier univariate analysis for the OS of k-means clusteringdefined groups of patients with MM (776 patients in total). According to the American Cancer Society, screening can often find colorectal cancer early, before it has spread, making it easier to treat. New York: St. Martin's Press, 1995. Then in 2007, Lavender helped with another fundraiser for Hillary, this time as part of her first presidential bid. 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. (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. (D) Schematic representation of the glycolysis metabolic pathway and the TCA cycle. (B) GSEA enrichment plots show enrichment of the FOXO-regulated LE glycolysis, LE TCA cycle, and LE OXPHOS gene sets (supplemental Table1) in MM plasma cells from newly diagnosed patients (MMPCs, n= 75) compared with plasma cells from healthy donors (n= 15). Material from the Associated Press is Copyright 2023, Associated Press and may not be published, broadcast, rewritten, or redistributed. After a business trip in September 2012, however, she knew something was wrong. The official, Dr . [9] From February 1918 until October 1919, she provided James Joyce with a monthly benefaction. 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). (B) Basal glycolysis in HMCLs and MMPCs (n= 2 patients) treated with 2.5 M MK2206 (blue bars) for 20 hours or untreated (red bars). It's sad to know how brainwashed breast cancer awareness is about chemotherapy, radiation, and surgery. [12], Edith and Harold were divorced in December 1921. And she found out the hard way. (C) Linear regression analysis of the glycolytic reserve values (x-axis) vs the EC50 values for 2-DG (y-axis) in HMCLs and BCLs. To continue their mission today, Shah says the RF must "directly confront climate change". FOXO-dependent repression of metabolic genes is associated with favorable prognosis in MM. 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). When evidence began to emerge that petroleum based medicine was causing cancer, Rockefeller founded the American Cancer Society, through which he suppressed that information. (D) Fold change of ECAR, basal respiration, maximum respiration, and spare respiratory capacity (OCR) from a Seahorse XF mitochondrial stress test in HMCLs treated with DCA (25 mM for 20 hours) or cultured for 4 days in a galactose-containing medium (11.1 mM, no glucose). Here, we demonstrate that negative regulation of the forkhead box O (FOXO) transcription factors (TFs) by AKT is crucial to prevent the metabolic shutdown in MM cells, thus contributing to their metabolic adaptability. All flow cytometry data were obtained using a FACSCanto or LSR Fortessa (BD Biosciences, Franklin Lakes, NJ) and analyzed using FlowJo software (FlowJo, Ashland, OR). Mr. Rockefeller founded the American Cancer Society for which he surpressed that information. The Rockefeller Foundation (RF) entered China with an ambitious goal: to build modern medical schools in both Beijing and Shanghai. 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. "I remembered that I loved everything at UAMS then," she says. (A) Univariate analysis of subgroups (n= 776 patients; alternative numbers of patients indicated in case values/data were missing) for OS. [11] She returned to America in 1921 after an eightyear stay. Lavender was 42 when she was diagnosed. She and Harold, along with other wealthy patrons, founded the Grand Opera Company, the first in Chicago, in 1909. 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). "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.". These results indicate that AKT signaling is required to restrain the FOXO-dependent suppression of many key metabolic enzymes in MM cells. 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. She was a member of both the Young Democrats group and the Teenage Republicans. During the race for ASG president, Lavender says, her friend's opponent had more money and used it to make professional yard signs. John D. Rockefeller is also the son of the founder of the pharmaceutical industry in the US. 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. 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. 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). 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. -actin served as a loading control. 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. UAMS says the economic impact on Arkansas could be $72 million, with 1,500 new jobs created over five years. I want a nation of workers." Her longtime friend Keisha Merritt of Bentonville can attest to Lavender's persistence. In addition, AKT kinase activity regulated mitochondrial respiration in MM (Figure2C, supplemental Figure2E-F). "Having that many people there, it was just incredible.". These results suggest that AKT signaling might be a determinant of metabolic adaptability in MM cells. The article noted that she was "glad to be rid of the gay Harold McCormick, but hasn't succeeded in convincing her friends she will never marry again. While in college, she also worked on what she calls her first "real" political campaign when Sheffield Nelson ran against the incumbent governor, Bill Clinton, in the 1990 gubernatorial campaign. Univariate analysis showed that LE glycolysis (high), LE TCA (high), and LE OXPHOS (high) represent adverse features for OS (hazard ratios 1.6-1.7) in conjunction with other well-known adverse factors (Figure6A). Upon graduation, he moved his family to Texarkana, where he joined a local law firm. Margaret Higgins Sanger (born Margaret Louise Higgins; September 14, 1879 - September 6, 1966), also known as Margaret Sanger Slee, was an American birth control activist, sex educator, writer, and nurse.Sanger popularized the term "birth control", opened the first birth control clinic in the United States, and established organizations that evolved into the Planned Parenthood Federation of . We have previously shown that AKT regulates the stability of the antiapoptotic Myeloid-cell leukemia 1 (MCL-1) protein, which is essential for the survival of MM cells.18 Consequently, HMCLs overexpressing MCL-1 were resistant to AKT inhibitorinduced cell death.18 However, MCL-1 overexpression did not prevent reduced glycolysis induced by MK2206 treatment, indicating that the effects of AKT inhibition on glycolysis were not related to the induction of apoptosis (supplemental Figure2C). 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. The authors thank Berend Hooibrink (flow cytometry core facility, Amsterdam University Medical Centers) for excellent flow cytometry assistance. Longtime friends are not surprised at Lavender's dedication to colorectal cancer awareness and prevention. "It was a wonderful experience being on the 'Hill,'" she says. 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. That's for another blog post but here is a quote from John D. Rockefeller that summarizes his vision for . "It was a great place to grow up." To her surprise, she didn't return home to Little Rock until Dec. 13, and then for only a short stay, and had to miss Christmas with her family. Her friend won. Her three elder sisters were Elizabeth (Bessie) (18661906), Alice (18691870), and Alta (18711962). "It was a fabulous environment that day," Lavender says, noting that more than 1,000 people participated in 2022. In high school, Lavender was very involved in "almost every activity," she says. P-values were determined with Wald 2 test in Cox regression analysis. Born into modest circumstances in upstate New York, he. In addition, regular screening can prevent colorectal cancer by allowing doctors to find and remove polyps before they turn into cancer. (B) Half maximal effective concentrations (EC50) of 2-DG for cell death in HMCLs and BCLs after 3 days of treatment. Our results suggest that the expression of a subset of metabolic genes is an important output parameter of AKT signaling, which crucially impacts the malignant behavior of MM cells and represents an independent adverse feature. Mean values of 3 individual experiments are depicted. 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. Protein expression of the glycolysis rate-limiting enzyme HK2 was decreased upon MK2206 treatment, whereas the effects on pyruvate kinase M2 (PKM2) were modest (Figure2A). Z-score values are depicted, ranging from3 (blue) indicating low expression to 3 (red) indicating high expression. 1.8K views, 91 likes, 68 loves, 461 comments, 162 shares, Facebook Watch Videos from Stop the Rot Sack the Lot: Live chat with Guru and Cazz by Together, these results show that AKT crucially regulates the metabolic functioning of MM cells by controlling the activity of FOXO. The protein kinase B/AKT acts as a central node in cellular metabolism and is constitutively active in MM cells. The plan fell through for undisclosed reasons in December 1922. Tera Futrell Kesterson of Nashville in Howard County, who met Lavender in college as Chi Omega sorority sisters, says Lavender is a "great friend" to many and inspired others with her courage, especially during her recovery from colorectal cancer. "It was the campaign part that was the fun part for me," she says. "[17] She was also said to be interested in astrology and to celebrate Christmas on December 15. She is especially interested in raising awareness of early onset colorectal cancer, which occurs in people under age 45 and is on the rise. . (C) Basal respiration and spare respiratory capacity in HMCLs and MMPCs (n= 2 patients) treated with 2.5 M MK2206 (blue bars) or untreated(red bars) for 20 hours. 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. 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. At the time of her death, her estate, through the Edith Rockefeller McCormick Trust set up by her father in 1923, consisted mostly of real estate and no longer held much Standard Oil stock. In that respect, (combinatorial) targeting of signaling pathways that regulate metabolic plasticity may be a preferred approach, placing the AKT kinase in the limelight again, where the prevention of feedback regulation and/or activation of salvage pathways will be key for a successful therapeutic modality.