[en] Propranolol, a widely used non-selective beta-adrenergic receptor blocker, was recently shown to display anticancer properties. Its potential to synergize with certain drugs has been also outlined. However, it is necessary to take into account all the properties of propranolol to select a drug that could be efficiently combined with. Propranolol was reported to block the late phase of autophagy. Hence, we hypothesized that in condition enhancing autophagy flux, cancer cells should be especially sensitive to propranolol. 2DG, a glycolysis inhibitor, is an anti-tumor agent having limited effect in monotherapy notably due to induction of pro-survival autophagy. Here, we report that treatment of cancer cells with propranolol in combination with the glycolysis inhibitor 2DG induced a massive accumulation of autophagosome due to autophagy blockade. The propranolol +2DG treatment efficiently prevents prostate cancer cell proliferation, induces cell apoptosis, alters mitochondrial morphology, inhibits mitochondrial bioenergetics and aggravates ER stress in vitro and also suppresses tumor growth in vivo. Our study underlines for the first time the interest to take advantage of the ability of propranolol to inhibit autophagy to design new anti-cancer therapies.
Research center :
Giga-Cancer - ULiège
Disciplines :
Oncology
Author, co-author :
Brohée, Laura ; Université de Liège - ULiège > GIGA-Cancer > Laboratoire de Biologie des Tissus Conjonctifs
Peulen, Olivier ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Nusgens, Betty ; Université de Liège - ULiège > Sciences Biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Thiry, Marc ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie cellulaire
Colige, Alain ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs
Deroanne, Christophe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs
Language :
English
Title :
Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression.
Roles of lipins in cancer progression and analysis of their potential as targets for cancer therapy
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] ULiège - Université de Liège [BE] CAC - Centre anticancéreux près l'Université de Liège asbl [BE]
Hanahan, D. Rethinking the war on cancer. Lancet 383, 558-563, https://doi.org/10.1016/S0140-6736(13)62226-6 (2014).
Furuta, E., Okuda, H., Kobayashi, A. &Watabe, K. Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim Biophys Acta 1805, 141-152, https://doi.org/10.1016/j.bbcan.2010.01.005 (2010).
Brohee, L. et al. Lipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment. Oncotarget 6, 11264-11280, https://doi.org/10.18632/oncotarget.3595 (2015).
Zhang, P. &Reue, K. Lipin proteins and glycerolipid metabolism: Roles at the ER membrane and beyond. Biochim Biophys Acta. https://doi.org/10.1016/j.bbamem.2017.04.007 (2017).
Zhang, P., Verity, M. A. &Reue, K. Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle. Cell Metab 20, 267-279, https://doi.org/10.1016/j.cmet.2014.05.003 (2014).
Amaravadi, R., Kimmelman, A. C. &White, E. Recent insights into the function of autophagy in cancer. Genes Dev 30, 1913-1930, https://doi.org/10.1101/gad.287524.116 (2016).
DiPaola, R. S. et al. Therapeutic starvation and autophagy in prostate cancer: a new paradigm for targeting metabolism in cancer therapy. Prostate 68, 1743-1752, https://doi.org/10.1002/pros.20837 (2008).
Kimmelman, A. C. &White, E. Autophagy and Tumor Metabolism. Cell Metab 25, 1037-1043, https://doi.org/10.1016/j. cmet.2017.04.004 (2017).
Amaravadi, R. K. et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 17, 654-666, https://doi.org/10.1158/1078-0432.CCR-10-2634 (2011).
Rebecca, V. W. &Amaravadi, R. K. Emerging strategies to effectively target autophagy in cancer. Oncogene 35, 1-11, https://doi. org/10.1038/onc.2015.99 (2016).
Frishman, W. H. Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well. Prog Cardiovasc Dis 59, 247-252, https://doi. org/10.1016/j.pcad.2016.10.005 (2016).
Hardison, S., Wan, W. &Dodson, K. M. The use of propranolol in the treatment of subglottic hemangiomas: A literature review and meta-analysis. Int J Pediatr Otorhinolaryngol 90, 175-180, https://doi.org/10.1016/j.ijporl.2016.09.012 (2016).
Laken, P. A. Infantile Hemangiomas: Pathogenesis and Review of Propranolol Use. Adv Neonatal Care 16, 135-142, https://doi. org/10.1097/ANC.0000000000000254 (2016).
Farah, B. L. et al. beta-Adrenergic agonist and antagonist regulation of autophagy in HepG2 cells, primary mouse hepatocytes, and mouse liver. PLoS One 9, e98155, https://doi.org/10.1371/journal.pone.0098155 (2014).
Chang, P. Y. et al. Propranolol Reduces Cancer Risk: A Population-Based Cohort Study. Medicine (Baltimore) 94, e1097, https://doi. org/10.1097/MD.0000000000001097 (2015).
Brown, J. Effects of 2-deoxyglucose on carbohydrate metablism: review of the literature and studies in the rat. Metabolism 11, 1098-1112 (1962).
Wick, A. N., Drury, D. R., Nakada, H. I. &Wolfe, J. B. Localization of the primary metabolic block produced by 2-deoxyglucose. J Biol Chem 224, 963-969 (1957).
Kovacs, K. et al. 2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N-Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3beta Activation. Mol Cancer Ther 15, 264-275, https://doi.org/10.1158/1535-7163.MCT-14-0315 (2016).
Xi, H. et al. 2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemother Pharmacol 67, 899-910, https://doi.org/10.1007/s00280-010-1391-0 (2011).
Zhang, D. et al. 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett 355, 176-183, https://doi.org/10.1016/j.canlet.2014.09.003 (2014).
Ben Sahra, I. et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res 70, 2465-2475, https://doi.org/10.1158/0008-5472.CAN-09-2782 (2010).
Giammarioli, A. M. et al. Differential effects of the glycolysis inhibitor 2-deoxy-D-glucose on the activity of pro-apoptotic agents in metastatic melanoma cells, and induction of a cytoprotective autophagic response. Int J Cancer 131, E337-347, https://doi. org/10.1002/ijc.26420 (2012).
Zadra, G., Photopoulos, C. &Loda, M. The fat side of prostate cancer. Biochim Biophys Acta 1831, 1518-1532, https://doi. org/10.1016/j.bbalip.2013.03.010 (2013).
Singh, K. et al. Autophagic flux determines cell death and survival in response to Apo2L/TRAIL (dulanermin). Mol Cancer 13, 70, https://doi.org/10.1186/1476-4598-13-70 (2014).
Maccari, S. et al. Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice. Br J Pharmacol 174, 139-149, https://doi.org/10.1111/bph.13662 (2017).
Pasquier, E. et al. Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget 2, 797-809, https://doi.org/10.18632/oncotarget.343 (2011).
Wolter, J. K. et al. Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma. Oncotarget 5, 161-172, https://doi.org/10.18632/oncotarget.1083 (2014).
Rico, M. et al. Metformin and propranolol combination prevents cancer progression and metastasis in different breast cancer models. Oncotarget 8, 2874-2889, https://doi.org/10.18632/oncotarget.13760 (2017).
Albert, D. et al. The role of diacylglyceride generation by phospholipase D and phosphatidic acid phosphatase in the activation of 5-lipoxygenase in polymorphonuclear leukocytes. J Leukoc Biol 83, 1019-1027, https://doi.org/10.1189/jlb.0807531 (2008).
Grkovich, A., Johnson, C. A., Buczynski, M. W. &Dennis, E. A. Lipopolysaccharide-induced cyclooxygenase-2 expression in human U937 macrophages is phosphatidic acid phosphohydrolase-1-dependent. J Biol Chem 281, 32978-32987, https://doi.org/10.1074/ jbc.M605935200 (2006).
Han, G. S. &Carman, G. M. Characterization of the human LPIN1-encoded phosphatidate phosphatase isoforms. J Biol Chem 285, 14628-14638, https://doi.org/10.1074/jbc.M110.117747 (2010).
He, J. et al. Lipin-1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triplenegative breast cancer cell survival. FASEB J 31, 2893-2904, https://doi.org/10.1096/fj.201601353R (2017).
Kim, J. Y., Kim, G., Lim, S. C. &Choi, H. S. LPIN1 promotes epithelial cell transformation and mammary tumourigenesis via enhancing insulin receptor substrate 1 stability. Carcinogenesis 37, 1199-1209, https://doi.org/10.1093/carcin/bgw104 (2016).
Schonthal, A. H. Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem Pharmacol 85, 653-666, https://doi.org/10.1016/j.bcp.2012.09.012 (2013).
Choi, S. Y. et al. A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat Cell Biol 8, 1255-1262, https://doi.org/10.1038/ncb1487 (2006).
Huang, H. et al. piRNA-associated germline nuage formation and spermatogenesis require MitoPLD profusogenic mitochondrialsurface lipid signaling. Dev Cell 20, 376-387, https://doi.org/10.1016/j.devcel.2011.01.004 (2011).
Kavaliauskiene, S. et al. Novel actions of 2-deoxy-D-glucose: protection against Shiga toxins and changes in cellular lipids. Biochem J 470, 23-37, https://doi.org/10.1042/BJ20141562 (2015).
Saotome, M. et al. Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci USA 105, 20728-20733, https://doi.org/10.1073/pnas.0808953105 (2008).
Pantziarka, P. et al. Repurposing Drugs in Oncology (ReDO)-Propranolol as an anti-cancer agent. Ecancermedicalscience 10, 680, https://doi.org/10.3332/ecancer.2016.680 (2016).
Farrow, J. M., Yang, J. C. &Evans, C. P. Autophagy as a modulator and target in prostate cancer. Nat Rev Urol 11, 508-516, https:// doi.org/10.1038/nrurol.2014.196 (2014).
Deroanne, C. F., Lapiere, C. M. &Nusgens, B. V. In vitro tubulogenesis of endothelial cells by relaxation of the coupling extracellular matrix-cytoskeleton. Cardiovasc Res 49, 647-658 (2001).
Labarca, C. &Paigen, K. A simple, rapid, and sensitive DNA assay procedure. Anal Biochem 102, 344-352 (1980).
Deroanne, C. F., Colige, A. C., Nusgens, B. V. &Lapiere, C. M. Modulation of expression and assembly of vinculin during in vitro fibrillar collagen-induced angiogenesis and its reversal. Exp Cell Res 224, 215-223, https://doi.org/10.1006/excr.1996.0131 (1996).
N'Diaye, E. N. et al. PLIC proteins or ubiquilins regulate autophagy-dependent cell survival during nutrient starvation. EMBO Rep 10, 173-179, https://doi.org/10.1038/embor.2008.238 (2009).
Pike Winer, L. S. &Wu, M. Rapid analysis of glycolytic and oxidative substrate flux of cancer cells in a microplate. PLoS One 9, e109916, https://doi.org/10.1371/journal.pone.0109916 (2014).
