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  • br Herrmann R Bodoky G Ruhstaller T Glimelius B

    2020-08-12


    [29] Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schuller J, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pan-creatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clin-ical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 2007 Jun 1;25(16):2212–7.
    [32] Fest J, Ruiter R, van Rooij FJ, van der Geest LG, Lemmens VE, Ikram MA, et al. Under-estimation of pancreatic cancer in the national cancer registry - reconsidering the in-cidence and survival rates. Eur J Cancer 2017 Feb;72:186–91.
    [33] Barbas AS, Turley RS, Ceppa EP, Reddy SK, Blazer III DG, Clary BM, et al. Comparison of outcomes and the use of multimodality therapy in young and elderly people un-dergoing surgical resection of pancreatic cancer. J Am Geriatr Soc 2012 Feb;60(2): 344–50.
    [34] Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal tumor study group. Cancer 1987 Jun 15;59(12):2006–10.
    [35] Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 1997 May;225(5):621–33.
    [36] Klinkenbijl JH, Jeekel J, Sahmoud T, van PR, Couvreur ML, Veenhof CH, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999 Dec;230(6):776–82. [37] Baldini C, Escande A, Bouche O, El-Hajbi F, Bourgeois V, Renaut Ventroys T, et al. Folfirinage: tolerance and efficacy of folfirinox in elderly patients with metastatic 
    Abstract].
    [39] Vijayvergia N, Dotan E, Devarajan K, Hatahet K, Rahman F, Ricco J, et al. Patterns of care and outcomes of older versus younger patients with metastatic pancreatic can-cer: a Fox Chase Cancer Center experience. J Geriatr Oncol 2015 Nov;6(6):454–61.
    [45] Pignay-Demaria V, Lesperance F, Demaria RG, Frasure-Smith N, Perrault LP. Depres-sion and anxiety and outcomes of coronary artery bypass surgery. Ann Thorac Surg 2003 Jan;75(1):314–21.
    Contents lists available at ScienceDirect
    Biochemical Pharmacology
    journal homepage: www.elsevier.com/locate/biochempharm
    An N6-methyladenosine at the transited Glycols polyethylene 273 of p53 pre-mRNA T
    promotes the expression of R273H mutant protein and drug resistance of
    cancer cells
    Mohammad B. Uddin a,1, Kartik R. Roya, Salman B. Hosaina, Sachin K. Khistea, Ronald A. Hilla, Seetharama D. Joisa, Yunfeng Zhaob, Alan J. Tackettc, Yong-Yu Liua, a School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA b Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA c Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
    Keywords:
    Tumor suppressor p53
    Missense mutation
    RNA methylation
    N6-methyladenosine Drug resistance
    Glucosylceramide synthase 
    Mutant p53 proteins that promote cancer cell invasive growth, metastasis and drug resistance emerge as ther-apeutic targets. Previously, we reported that suppression of ceramide glycosylation restored wild-type p53 protein and tumor suppressing function in cancer cells heterozygously carrying p53 R273H, a hot-spot missense mutation; however, the mechanisms underlying the control of mutant protein expression remain elusive. Herein, we report that an N6-methyladenosine (m6A) at the point-mutated codon 273 (G > A) of p53 pre-mRNA de-termines the mutant protein expression. Methylation of the transited adenosine was catalyzed by methyl-transferase like 3 (METTL3), and this m6A-RNA promoted a preferential pre-mRNA splicing; consequently, the produced p53 R273H mutant protein resulted in acquired multidrug resistance in colon cancer cells. Furthermore, glycosphingolipids (particularly globotriaosylceramide) generated from serial ceramide glycosy-lation were seen to activate cSrc and β-catenin signaling so as to upregulate METTL3 expression, in turn pro-moting expression of p53 R273H mutant protein, with consequent drug resistance. Conversely, either silencing METTL3 expression by using small interfering RNA (siRNA) or inhibiting RNA methylation with neplanocin A suppressed m6A formation in p53 pre-mRNA, and substantially increased the level of phosphorylated p53 protein (Ser15) and its function in cells heterozygously carrying the R273H mutation, thereby re-sensitizing these cells to anticancer drugs. Concordantly, suppression of ceramide glycosylation repressed METTL3 ex-pression and m6A formation in p53 pre-mRNA, thus sensitizing cells carrying R273H to anticancer drugs. This study uncovers a novel function of pre-mRNA m6A as a determinant of mutant protein expression in cancer cells heterozygously carrying the TP53 R273H mutation. Suppressing both RNA methylation and ceramide glycosy-lation might constitute an efficacious and specific approach for targeting TP53 missense mutations coding for a G > A transition, thereby improving cancer treatments.