Treatment of cells with chemotherapy drugs activates the intrinsic mitochondrial pathway of apoptosis and the caspase protease cascade. Recently, the lysosomal protease cathepsin D has been implicated in apoptosis caused by oxidative stress, inhibition of protein kinase C, and stimulation of the TNFR1 and Fas death receptors.
The production of mature, differentiated myeloid cells is regulated by the action of hematopoietic cytokines on progenitor cells in the bone marrow. Cytokines drive the process of myeloid differentiation by binding to specific cell-surface receptors in a stage-and lineage-specific manner. Following the binding of a cytokine to its cognate receptor, intracellular signal-transduction pathways become activated that facilitate the myeloid differentiation process. These intracellular signaling pathways may promote myelopoiesis by stimulating expansion of a progenitor pool, supporting cellular survival during the differentiation process, or by directly driving the phenotypic changes associated with differentiation. Ultimately, pathways that drive the differentiation process converge on myeloid transcription factors, including PU.1 and the C/EBP family, that are critical for differentiation to proceed. While much is known about the cytokines, cytokine receptors and transcription factors that regulate myeloid differentiation, less is known about the precise roles that specific signaling mediators play in promoting myeloid differentiation. Recently, however, the application of novel pharmacologic inhibitors, siRNA strategies, and transgenic and knockout models has begun to shed light on the involvement and function of signaling pathways in normal myeloid differentiation. This review will discuss the roles that key signaling pathways and mediators play in myeloid differentiation.
Head and neck squamous cell carcinomas (HNSCC) are frequently characterized by chemotherapy and radiation resistance, and by overexpression of Bcl-XL, an antiapoptotic member of the Bcl-2 protein family. In this report we examined whether cell-permeable peptides derived from the BH3 domains of proapoptotic Bax, Bad, or Bak could be used to target Bcl-XL and/or Bcl-2 in HNSCC cells, and induce apoptotic death in these cells. To render the peptides cell permeable, Antennapedia (Ant) or polyarginine (R8) peptide transduction domains were fused to the amino termini. Fluorescence microscopy of peptide-treated HNSCC cells revealed that the BH3 peptides colocalized with mitochondria, the site of Bcl-XL and Bcl-2 expression. By contrast, a mutant peptide (BaxE BH3) which cannot bind Bcl-XL or Bcl-2 was diffusely localized throughout the cytoplasm. Treatment of three HNSCC cell lines (1483, UM-22A, UM-22B) with the wild-type BH3 peptides resulted in loss of viability and induction of apoptosis, as assessed by MTS assays and annexin V staining. In general, Ant-conjugated peptides were more potent than R8-conjugated peptides, and Bad BH3 peptide was typically more potent than Bax BH3 or Bak BH3. Treatment of purified HNSCC mitochondria with BH3 peptides resulted in robust release of cytochrome c. Thus, the relative apoptosis resistance of HNSCC cells is not due to a deficit in this step of the intrinsic, mitochondrial-mediated apoptosis pathway. We conclude that cell-permeable BH3 peptides can be used to target Bcl-XL and/or Bcl-2 in HNSCC, and targeting of these proteins may have therapeutic value in the treatment of this disease.
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