Non-genomic events determining the sensitivity of hemopoietic malignancies to glucocorticoid-induced apoptosis
- 451 Downloads
Glucocorticoid (GC) hormones have been introduced as therapeutic agents in blood cancers six decades ago. The effectiveness of GC treatment stems from its ability to induce apoptotic death of hemopoietic cells. A major impediment in GC therapy is the acquisition of resistance to the drug upon repeated treatment. In addition, some blood cancers are a priori resistant to GC therapy. Usually, resistance to GC correlates with poor prognosis. Albeit the wide use of GC in clinical practice, their mode of action is not fully understood. The cellular response to GC is initiated by its binding to the cytosolic GC receptor (GR) that translocates to the nucleus and modulates gene expression. However, nuclear activities of GR occur in both apoptosis-sensitive and apoptosis-resistant cells. These apparent controversies can be resolved by deciphering non-genomic effects of GCs and the mode by which they modulate the apoptotic response. We suggest that non-genomic consequences of GC stimulation determine the cell fate toward survival or death. Understanding the cellular mechanisms of GC apoptotic sensitivity contributes to the development of new modalities for overcoming GC resistance.
KeywordsGlucocorticoids Hemopoietic tumors Mitochondria BIM Glycogen synthase kinase 3 CITIM 2013
The authors wish to thank Dr. Ronit Vogt-Sionov, Hali Spokoini, and Prof. Ingrid Herr for their contribution. The study described in this review was supported in part by the German-Israel Foundation (GIF) and Concern Foundation.
Conflict of interest
The authors declare that they have no conflict of interest.
- 3.Kfir-Erenfeld S, Sionov RV, Spokoini R, Cohen O, Yefenof E (2010) Protein kinase networks regulating glucocorticoid-induced apoptosis of hematopoietic cancer cells: fundamental aspects and practical considerations. Leuk Lymphoma 51(11):1968–2005. doi: 10.3109/10428194.2010.506570 PubMedCrossRefGoogle Scholar
- 7.Talaber G, Boldizsar F, Bartis D, Palinkas L, Szabo M, Berta G, Setalo G Jr, Nemeth P, Berki T (2009) Mitochondrial translocation of the glucocorticoid receptor in double-positive thymocytes correlates with their sensitivity to glucocorticoid-induced apoptosis. Int Immunol 21(11):1269–1276. doi: 10.1093/intimm/dxp093 PubMedCrossRefGoogle Scholar
- 16.Urbich C, Knau A, Fichtlscherer S, Walter DH, Bruhl T, Potente M, Hofmann WK, de Vos S, Zeiher AM, Dimmeler S (2005) FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J 19(8):974–976. doi: 10.1096/fj.04-2727fje PubMedGoogle Scholar
- 24.Laane E, Panaretakis T, Pokrovskaja K, Buentke E, Corcoran M, Soderhall S, Heyman M, Mazur J, Zhivotovsky B, Porwit A, Grander D (2007) Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members. Haematologica 92(11):1460–1469. doi: 10.3324/haematol.10543 PubMedCrossRefGoogle Scholar
- 25.Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig TA, Bouchard RJ, Florez-McClure ML, Heidenreich KA (2004) Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 24(44):9993–10002. doi: 10.1523/JNEUROSCI.2057-04.2004 PubMedCrossRefGoogle Scholar
- 26.Pastorino JG, Hoek JB, Shulga N (2005) Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 65(22):10545–10554. doi: 10.1158/0008-5472.CAN-05-1925 PubMedCrossRefGoogle Scholar
- 27.Sade H, Khandre NS, Mathew MK, Sarin A (2004) The mitochondrial phase of the glucocorticoid-induced apoptotic response in thymocytes comprises sequential activation of adenine nucleotide transporter (ANT)-independent and ANT-dependent events. Eur J Immunol 34(1):119–125. doi: 10.1002/eji.200324650 PubMedCrossRefGoogle Scholar
- 32.Ogawa M, Nishiura T, Oritani K, Yoshida H, Yoshimura M, Okajima Y, Ishikawa J, Hashimoto K, Matsumura I, Tomiyama Y, Matsuzawa Y (2000) Cytokines prevent dexamethasone-induced apoptosis via the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in a new multiple myeloma cell line. Cancer Res 60(15):4262–4269PubMedGoogle Scholar