Protein kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia.
Bone Marrow Cells
/ drug effects
Cell Communication
/ drug effects
Cell Survival
/ drug effects
Glucose
/ metabolism
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
Mesenchymal Stem Cells
/ drug effects
Protein Kinase C beta
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Tumor Microenvironment
/ drug effects
Bone marrow stromal cells
PKCβ
chronic lymphocytic leukemia
glucose metabolism
Journal
Stem cells (Dayton, Ohio)
ISSN: 1549-4918
Titre abrégé: Stem Cells
Pays: England
ID NLM: 9304532
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
09
10
2020
accepted:
15
01
2021
pubmed:
5
2
2021
medline:
15
12
2021
entrez:
4
2
2021
Statut:
ppublish
Résumé
Survival of chronic lymphocytic leukemia (CLL) cells critically depends on the support of an adapted and therefore appropriate tumor microenvironment. Increasing evidence suggests that B-cell receptor-associated kinases such as protein kinase C-β (PKCβ) or Lyn kinase are essential for the formation of a microenvironment supporting leukemic growth. Here, we describe the impact of PKCβ on the glucose metabolism in bone marrow stromal cells (BMSC) upon CLL contact. BMSC get activated by CLL contact expressing stromal PKCβ that diminishes mitochondrial stress and apoptosis in CLL cells by stimulating glucose uptake. In BMSC, the upregulation of PKCβ results in increased mitochondrial depolarization and leads to a metabolic switch toward oxidative phosphorylation. In addition, PKCβ-deficient BMSC regulates the expression of Hnf1 promoting stromal insulin signaling after CLL contact. Our data suggest that targeting PKCβ and the glucose metabolism of the leukemic niche could be a potential therapeutic strategy to overcome stroma-mediated drug resistance.
Substances chimiques
Protein Kinase Inhibitors
0
PRKCB protein, human
EC 2.7.11.13
Protein Kinase C beta
EC 2.7.11.13
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
819-830Subventions
Organisme : Austrian Science Fund FWF
ID : I 3282
Pays : Austria
Informations de copyright
© 2021 The Authors. Stem Cells published by Wiley Periodicals LLC on behalf of AlphaMed Press 2021.
Références
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42. https://doi.org/10.1056/NEJMoa1215637.
Burger JA, Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 2013;34(12):592-601. https://doi.org/10.1016/j.it.2013.07.002.
Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood. 2013;122(23):3723-3734. https://doi.org/10.1182/blood-2013-05-498287.
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322. https://doi.org/10.1056/NEJMoa1513257.
Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114(16):3367-3375. https://doi.org/10.1182/blood-2009-06-225326.
ten Hacken E, Burger JA. Microenvironment dependency in chronic lymphocytic leukemia: the basis for new targeted therapies. Pharmacol Ther. 2014;144(3):338-348. https://doi.org/10.1016/j.pharmthera.2014.07.003.
Galletti G, Scielzo C, Barbaglio F, et al. Targeting macrophages sensitizes chronic lymphocytic leukemia to apoptosis and inhibits disease progression. Cell Rep. 2016;14(7):1748-1760. https://doi.org/10.1016/j.celrep.2016.01.042.
Lutzny G, Kocher T, Schmidt-Supprian M, et al. Protein kinase c-beta-dependent activation of NF-kappaB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo. Cancer Cell. 2013;23(1):77-92. https://doi.org/10.1016/j.ccr.2012.12.003.
Qorraj M, Bruns H, Bottcher M, et al. The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia. Leukemia. 2017;31(2):470-478. https://doi.org/10.1038/leu.2016.214.
Jitschin R, Braun M, Qorraj M, et al. Stromal cell-mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling. Blood. 2015;125(22):3432-3436. https://doi.org/10.1182/blood-2014-10-607036.
Pascutti MF, Jak M, Tromp JM, et al. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood. 2013;122(17):3010-3019. https://doi.org/10.1182/blood-2012-11-467670.
Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell'Aquila M, Kipps TJ. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood. 2000;96(8):2655-2663.
Reinart N, Nguyen PH, Boucas J, et al. Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor. Blood. 2013;121(5):812-821. https://doi.org/10.1182/blood-2012-05-431452.
Rawstron AC, Kennedy B, Evans PA, et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood. 2001;98(1):29-35. https://doi.org/10.1182/blood.v98.1.29.
Pallasch CP, Leskov I, Braun CJ, et al. Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell. 2014;156(3):590-602. https://doi.org/10.1016/j.cell.2013.12.041.
Takai Y, Kishimoto A, Kikkawa U, Mori T, Nishizuka Y. Unsaturated diacylglycerol as a possible messenger for the activation of calcium-activated, phospholipid-dependent protein kinase system. Biochem Biophys Res Commun. 1979;91(4):1218-1224. https://doi.org/10.1016/0006-291x(79)91197-5.
Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984;308(5961):693-698. https://doi.org/10.1038/308693a0.
Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J. 1995;9(7):484-496.
Hug H, Sarre TF. Protein kinase C isoenzymes: divergence in signal transduction? Biochem J. 1993;291(Pt 2):329-343. https://doi.org/10.1042/bj2910329.
Su TT, Guo B, Kawakami Y, et al. PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol. 2002;3(8):780-786. https://doi.org/10.1038/ni823.
Tsui C, Martinez-Martin N, Gaya M, et al. Protein kinase C-beta dictates B cell fate by regulating mitochondrial remodeling, metabolic reprogramming, and heme biosynthesis. Immunity. 2018;48(6):1144-1159 e5. https://doi.org/10.1016/j.immuni.2018.04.031.
Nguyen PH, Fedorchenko O, Rosen N, et al. Kinase in the tumor microenvironment is essential for the progression of chronic lymphocytic leukemia. Cancer Cell. 2016;30(4):610-622. https://doi.org/10.1016/j.ccell.2016.09.007.
Tabit CE, Shenouda SM, Holbrook M, et al. Protein kinase C-beta contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation. 2013;127(1):86-95. https://doi.org/10.1161/CIRCULATIONAHA.112.127514.
Mehta KD. Emerging role of protein kinase C in energy homeostasis: a brief overview. World J Diabetes. 2014;5(3):385-392. https://doi.org/10.4239/wjd.v5.i3.385.
Bosch RR, Bazuine M, Span PN, et al. Regulation of GLUT1-mediated glucose uptake by PKClambda-PKCbeta(II) interactions in 3T3-L1 adipocytes. Biochem J. 2004;384(Pt 2):349-355. https://doi.org/10.1042/BJ20040797.
Oostendorp RA, Harvey KN, Kusadasi N, et al. Stromal cell lines from mouse aorta-gonads-mesonephros subregions are potent supporters of hematopoietic stem cell activity. Blood. 2002;99(4):1183-1189. https://doi.org/10.1182/blood.v99.4.1183.
Osterhoff MA, Heuer S, Pfeiffer M, et al. Identification of a functional protein kinase Cbeta promoter polymorphism in humans related to insulin resistance. Mol Genet Metab. 2008;93(2):210-215. https://doi.org/10.1016/j.ymgme.2007.09.004.
Adekola KU, Dalva Aydemir S, Ma S, Zhou Z, Rosen ST, Shanmugam M. Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin. Leuk Lymphoma. 2015;56(2):450-459. https://doi.org/10.3109/10428194.2014.922180.
Huang W, Bansode R, Mehta M, Mehta KD. Loss of protein kinase Cbeta function protects mice against diet-induced obesity and development of hepatic steatosis and insulin resistance. Hepatology. 2009;49(5):1525-1536. https://doi.org/10.1002/hep.22815.
Zhang W, Trachootham D, Liu J, et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat Cell Biol. 2012;14(3):276-286. https://doi.org/10.1038/ncb2432.
Standaert ML, Bandyopadhyay G, Galloway L, et al. Effects of knockout of the protein kinase C beta gene on glucose transport and glucose homeostasis. Endocrinology. 1999;140(10):4470-4477. https://doi.org/10.1210/endo.140.10.7073.
Hileman EO, Liu J, Albitar M, Keating MJ, Huang P. Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity. Cancer Chemother Pharmacol. 2004;53(3):209-219. https://doi.org/10.1007/s00280-003-0726-5.
Jitschin R, Hofmann AD, Bruns H, et al. Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia. Blood. 2014;123(17):2663-2672. https://doi.org/10.1182/blood-2013-10-532200.
Trachootham D, Zhang H, Zhang W, et al. Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism. Blood. 2008;112(5):1912-1922. https://doi.org/10.1182/blood-2008-04-149815.
Zhou Y, Hileman EO, Plunkett W, Keating MJ, Huang P. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood. 2003;101(10):4098-4104. https://doi.org/10.1182/blood-2002-08-2512.
Zhou Y, Tozzi F, Chen J, et al. Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 2012;72(1):304-314. https://doi.org/10.1158/0008-5472.CAN-11-1674.
Richter C, Juan MH, Will J, et al. Ncf1 provides a reactive oxygen species-independent negative feedback regulation of TLR9-induced IL-12p70 in murine dendritic cells. J Immunol. 2009;182(7):4183-4191. https://doi.org/10.4049/jimmunol.0800795.
Zheng K, Li Y, Wang S, et al. Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint. Autophagy. 2016;12(9):1593-1613. https://doi.org/10.1080/15548627.2016.1192751.
Ding W, Nowakowski GS, Knox TR, et al. Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression. Br J Haematol. 2009;147(4):471-483. https://doi.org/10.1111/j.1365-2141.2009.07868.x.
Vogler M, Butterworth M, Majid A, et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood. 2009;113(18):4403-4413. https://doi.org/10.1182/blood-2008-08-173310.
Marquez ME, Hernandez-Uzcategui O, Cornejo A, Vargas P, Da Costa O. Bone marrow stromal mesenchymal cells induce down regulation of CD20 expression on B-CLL: implications for rituximab resistance in CLL. Br J Haematol. 2015;169(2):211-218. https://doi.org/10.1111/bjh.13286.
Bossenmaier B, Mosthaf L, Mischak H, Ullrich A, Haring HU. Protein kinase C isoforms beta 1 and beta 2 inhibit the tyrosine kinase activity of the insulin receptor. Diabetologia. 1997;40(7):863-866. https://doi.org/10.1007/s001250050761.
Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science. 1996;272(5262):728-731. https://doi.org/10.1126/science.272.5262.728.
Kleiman E, Carter G, Ghansah T, Patel NA, Cooper DR. Developmentally spliced PKCbetaII provides a possible link between mTORC2 and Akt kinase to regulate 3T3-L1 adipocyte insulin-stimulated glucose transport. Biochem Biophys Res Commun. 2009;388(3):554-559. https://doi.org/10.1016/j.bbrc.2009.08.063.
Liberman Z, Plotkin B, Tennenbaum T, Eldar-Finkelman H. Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase C betaII in the diabetic fat tissue. Am J Physiol Endocrinol Metab. 2008;294(6):E1169-E1177. https://doi.org/10.1152/ajpendo.00050.2008.
Park E, Chen J, Moore A, et al. Stromal cell protein kinase C-beta inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance. Sci Transl Med. 2020;12(526):1-17. https://doi.org/10.1126/scitranslmed.aax9340.
Mangolini M, Gotte F, Moore A, et al. Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia. Nat Commun. 2018;9(1):3839. https://doi.org/10.1038/s41467-018-06069-5.