Control of FLIP(L) expression and TRAIL resistance by the extracellular signal-regulated kinase1/2 pathway in breast epithelial cells.

Increased activation of the epidermal growth factor receptor (EGFR) is frequently observed in tumors, and inhibition of the signaling pathways originated in the EGFR normally renders tumor cells more sensitive to apoptotic stimuli. However, we show that inhibition of EGFR signaling in non-transformed breast epithelial cells by EGF deprivation or gefitinib, an inhibitor of EGFR tyrosine kinase, causes the upregulation of the long isoform of caspase-8 inhibitor FLICE-inhibitory protein (FLIP(L)) and makes these cells more resistant to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We demonstrate that the extracellular signal-regulated kinase (ERK)1/2 pathway plays a pivotal role in the regulation of FLIP(L) levels and sensitivity to TRAIL-induced apoptosis by EGF. Upregulation of FLIP(L) upon EGF deprivation correlates with a decrease in c-Myc levels and c-Myc knockdown by siRNA induces FLIP(L) expression. FLIP(L) upregulation and resistance to TRAIL in EGF-deprived cells are reversed following activation of an estrogen activatable form of c-Myc (c-Myc-ER). Finally, constitutive activation of the ERK1/2 pathway in HER2/ERBB2-transformed cells prevents EGF deprivation-induced FLIP(L) upregulation and TRAIL resistance. Collectively, our results suggest that a regulated ERK1/2 pathway is crucial to control FLIP(L) levels and sensitivity to TRAIL in non-transformed cells, and this mechanism may explain the increased sensitivity of tumor cells to TRAIL, in which the ERK1/2 pathway is frequently deregulated.

The therapeutic potential of TRAIL receptor signalling in cancer cells.

In tumour cells, activation of the apoptotic machinery by death receptor ligands of the tumour necrosis factor (TNF) receptor superfamily of cytokines represents a novel therapeutic strategy. However, systemic treatment of tumours with TNF-α and CD95 ligand may produce severe toxic effects. The tumour necrosis-related apoptosisinducing ligand (TRAIL) is a member of the TNF family capable of inducing apoptosis in a wide variety of cancer cells upon binding to pro-apoptotic receptors, while having no effect on the majority of normal human cells tested. Interestingly, preclinical studies in mice and nonhuman primates showed no systemic cytotoxicity upon injection of either recombinant TRAIL or agonistic TRAIL-receptor antibodies. Furthermore, these treatments have been shown to effectively suppress the growth of a range of tumour xenografts. Although unwanted effects of some TRAIL preparations have been reported in normal cells, the use of TRAIL receptor agonists could represent a suitable approach in cancer therapy. Here, we shall review our current understanding of apoptotic and non-apoptotic TRAIL signalling, the therapeutic potential of TRAIL-based approaches in cancer treatment, and the results of phase 1 and 2 clinical trials with recombinant TRAIL or agonistic TRAIL receptor antibodies, either as monotherapy or in combination with other chemotherapeutic agents.

The therapeutic potential of TRAIL receptor signalling in cancer cells

In tumour cells, activation of the apoptotic machinery by death receptor ligands of the tumour necrosis factor (TNF) receptor superfamily of cytokines represents a novel therapeutic strategy. However, systemic treatment of tumours with TNF-α and CD95 ligand may produce severe toxic effects. The tumour necrosis-related apoptosisinducing ligand (TRAIL) is a member of the TNF family capable of inducing apoptosis in a wide variety of cancer cells upon binding to pro-apoptotic receptors, while having no effect on the majority of normal human cells tested. Interestingly, preclinical studies in mice and nonhuman primates showed no systemic cytotoxicity upon injection of either recombinant TRAIL or agonistic TRAIL-receptor antibodies. Furthermore, these treatments have been shown to effectively suppress the growth of a range of tumour xenografts. Although unwanted effects of some TRAIL preparations have been reported in normal cells, the use of TRAIL receptor agonists could represent a suitable approach in cancer therapy. Here, we shall review our current understanding of apoptotic and non-apoptotic TRAIL signalling, the therapeutic potential of TRAIL-based approaches in cancer treatment, and the results of phase 1 and 2 clinical trials with recombinant TRAIL or agonistic TRAIL receptor antibodies, either as monotherapy or in combination with other chemotherapeutic agents (AU)