Protein kinase networks regulating glucocorticoid-induced apoptosis of hematopoietic cancer cells: Fundamental aspects and practical considerations

Glucocorticoids (GCs) are integral components in the treatment protocols of acute lymphoblastic leukemia, multiple myeloma, and non-Hodgkin lymphoma owing to their ability to induce apoptosis of these malignant cells. Resistance to GC therapy is associated with poor prognosis. Although they have been used in clinics for decades, the signal transduction pathways involved in GC-induced apoptosis have only partly been resolved. Accumulating evidence shows that this cell death process is mediated by a communication between nuclear GR affecting gene transcription of pro-apoptotic genes such as Bim, mitochondrial GR affecting the physiology of the mitochondria, and the protein kinase glycogen synthase kinase-3 (GSK3), which interacts with Bim following exposure to GCs. Prevention of Bim up-regulation, mitochondrial GR translocation, and/or GSK3 activation are common causes leading to GC therapy failure. Various protein kinases positively regulating the pro-survival Src-PI3K-Akt-mTOR and Raf-Ras-MEK-ERK signal cascades have been shown to be activated in malignant leukemic cells and antagonize GC-induced apoptosis by inhibiting GSK3 activation and Bim expression. Targeting these protein kinases has proven effective in sensitizing GR-positive malignant lymphoid cells to GC-induced apoptosis. Thus, intervening with the pro-survival kinase network in GC-resistant cells should be a good means of improving GC therapy of hematopoietic malignancies.