Non-genomic events determining the sensitivity of hemopoietic malignancies to glucocorticoid-induced apoptosis.
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.
The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, POB: 12272, 91120, Jerusalem, Israel, shlomit.kfir@mail.huji.ac.il.
Shlomit
S
Kfir-Erenfeld
Eitan
E
Yefenof
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D003600:Cytosol / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005938:Glucocorticoids / Q000737:chemistry*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000473:pathology* / Q000628:therapy*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D005938:Glucocorticoids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid; D038362:Glycogen Synthase Kinase 3