دورية أكاديمية
GFI1-Dependent Repression of SGPP1 Increases Multiple Myeloma Cell Survival.
العنوان: | GFI1-Dependent Repression of SGPP1 Increases Multiple Myeloma Cell Survival. |
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المؤلفون: | Petrusca DN; Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA., Mulcrone PL; Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA., Macar DA; Department of Biological Sciences, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15219, USA., Bishop RT; Department of Tumor Biology, H. Lee Moffitt Cancer Research Center and Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA., Berdyshev E; Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA., Suvannasankha A; Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA.; Richard L. Rodebush Veterans Affairs Medical Center, 1481 W 10th St., Indianapolis, IN 46202, USA., Anderson JL; Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA., Sun Q; Department of Medicine, Division of Hematology/Oncology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, UPMC Hillman Cancer Center Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213, USA., Auron PE; Department of Biological Sciences, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15219, USA., Galson DL; Department of Medicine, Division of Hematology/Oncology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, UPMC Hillman Cancer Center Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213, USA., Roodman GD; Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA.; Richard L. Rodebush Veterans Affairs Medical Center, 1481 W 10th St., Indianapolis, IN 46202, USA. |
المصدر: | Cancers [Cancers (Basel)] 2022 Feb 02; Vol. 14 (3). Date of Electronic Publication: 2022 Feb 02. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101526829 Publication Model: Electronic Cited Medium: Print ISSN: 2072-6694 (Print) Linking ISSN: 20726694 NLM ISO Abbreviation: Cancers (Basel) Subsets: PubMed not MEDLINE |
أسماء مطبوعة: | Original Publication: Basel, Switzerland : MDPI |
مستخلص: | Multiple myeloma (MM) remains incurable for most patients due to the emergence of drug resistant clones. Here we report a p53-independent mechanism responsible for Growth Factor Independence-1 (GFI1) support of MM cell survival by its modulation of sphingolipid metabolism to increase the sphingosine-1-phosphate (S1P) level regardless of the p53 status. We found that expression of enzymes that control S1P biosynthesis, SphK1 , dephosphorylation, and SGPP1 were differentially correlated with GFI1 levels in MM cells. We detected GFI1 occupancy on the SGGP1 gene in MM cells in a predicted enhancer region at the 5' end of intron 1, which correlated with decreased SGGP1 expression and increased S1P levels in GFI1 overexpressing cells, regardless of their p53 status. The high S1P:Ceramide intracellular ratio in MM cells protected c-Myc protein stability in a PP2A-dependent manner. The decreased MM viability by SphK1 inhibition was dependent on the induction of autophagy in both p53WT and p53mut MM. An autophagic blockade prevented GFI1 support for viability only in p53mut MM, demonstrating that GFI1 increases MM cell survival via both p53WT inhibition and upregulation of S1P independently. Therefore, GFI1 may be a key therapeutic target for all types of MM that may significantly benefit patients that are highly resistant to current therapies. |
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معلومات مُعتمدة: | R01 AR059679 (to DLG & GDR) United States AR NIAMS NIH HHS; I01 BX004514 United States BX BLRD VA; ( to PEA) The Interleukin Foundation , Denver CO; ACS-IRG # IRG-16-192-31 (to DNP) American Cancer Society; 2I01CX000623-05 (to GDR) VA Merit Review; R01 AR059679 United States AR NIAMS NIH HHS |
فهرسة مساهمة: | Keywords: GFI1; PP2A; S1P; SGPP1; c-Myc; multiple myeloma |
تواريخ الأحداث: | Date Created: 20220215 Latest Revision: 20220304 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC8833953 |
DOI: | 10.3390/cancers14030772 |
PMID: | 35159039 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2072-6694 |
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DOI: | 10.3390/cancers14030772 |