Death receptor signals to the mitochondria

Abstract

ACKNOWLEDGEMENTSThe suggestions of R. Shalini are most appreciated. Work in Khosravi-Far laboratory is supported by Public Health Service grant, 1 HL080192 from the National Institute of Health, DAMD, 17-02-10298 and DAMD, 17-02-10299 from the Department of Defense and RSG 03-012-01-CCG from American Cancer Society. Review Death Receptor Signals to Mitochondria ABSTRACTApoptosis is the best-characterized form of programmed cell death (PCD) and is of fundamental importance in tissue homeostasis. In mammalian systems, there are two major pathways that are involved in the initiation of apoptosis: the "extrinsic" death receptor pathway and the "intrinsic" mitochondrial pathway. Although these pathways act independently to initiate the death machinery in some cellular systems, in many cell types, including numerous tumor cells, there is delicate coordination and cross talk between the extrinsic and intrinsic pathways, which leads to the activation of the executioner caspase cascade. Additionally, there appears to be a fine balance between the caspasemediated arm of death receptor signaling that engages mitochondria and the caspaseindependent arm that promotes vacuole proliferation in many cells. Here, we review our current knowledge about the layers of complexity that are posed by the interactions between death receptor-induced pathways and how they influence mitochondria to regulate cellular life and death decisions.

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

“…faulty mitotic spindle) can activate the cell cycle arrest and even the apoptotic cascade, leading to cell death (Rowinsky, 2005;Siegel, 2006). Thus, the apoptotic machinery is an essential element of cell cycle checkpoints, protecting the integrity of multicellular organisms and allowing for selective removal of unwanted or damaged cells (Khosravi-Far and Esposti, 2004;Los and Gibson, 2005;Los et al, 1999). Apoptosis also plays an important role in the embryonic development, during the regulation of the immune response and in tissue homeostasis Khosravi-Far and Esposti, 2004;Okada and Mak, 2004;Oliver and Vallette, 2005).…”

“…Thus, the apoptotic machinery is an essential element of cell cycle checkpoints, protecting the integrity of multicellular organisms and allowing for selective removal of unwanted or damaged cells (Khosravi-Far and Esposti, 2004;Los and Gibson, 2005;Los et al, 1999). Apoptosis also plays an important role in the embryonic development, during the regulation of the immune response and in tissue homeostasis Khosravi-Far and Esposti, 2004;Okada and Mak, 2004;Oliver and Vallette, 2005). The induction of programmed cell death occurs via two major pathways: the death receptor-dependent (extrinsic) pathway through TNFfamily ligands, or via the mitochondrial (intrinsic) pathway induced by different factors such as UV radiation, chemotherapeutics, free radicals or DNA damage (Brouckaert et al, 2005;Los et al, 1995;Maddika et al, 2006).…”

“…The induction of programmed cell death occurs via two major pathways: the death receptor-dependent (extrinsic) pathway through TNFfamily ligands, or via the mitochondrial (intrinsic) pathway induced by different factors such as UV radiation, chemotherapeutics, free radicals or DNA damage (Brouckaert et al, 2005;Los et al, 1995;Maddika et al, 2006). The induction of apoptosis leads to cell blebbing, exposure of phosphatidylserine at the cell surface, reduction of cell size, shrinkage of the cell core, DNA condensation and the formation of apoptotic bodies (Darzynkiewicz et al, 1997;Khosravi-Far and Esposti, 2004).…”

“…This event results in the formation of the death-induced signaling complex (DISC), activation of caspase-8 (cysteinyl aspartate-specific protease) and triggering the proteolytic caspase cascade (Brouckaert et al, 2005). Alternatively active caspase-8 can cleave the Bcl2-homology domain 3 (BH3) of the protein BID (BH3-interacting-domain death agonist) into the active form tBid (truncated BID) which provides a cross-talk between the extrinsic (death receptor-activated) and intrinsic (mitochondrial) pathway (Khosravi-Far and Esposti, 2004;Siegel, 2006). Cleaved Bid acquires a strong propensity to mitochondria and promotes the mitochondrial permeability transition (Hengartner, 2000).…”

Sulforaphane potentiates oxaliplatin-induced cell growth inhibition in colorectal cancer cells via induction of different modes of cell death

“…At present, two major apoptosis pathways have been identified: the intrinsic or mitochondrial pathway and the extrinsic or death receptor-related pathway. While the extrinsic pathway is activated through cell surface death-receptors binding their respective cytokine ligands, such as TRAIL [17], the intrinsic pathway depends on mitochondrial membrane permeabilization, which causes the release of apoptogenic factors from the intermembrane space to the cytoplasm. Prevalently, both pathways result in the activation of members of the caspase family converging at the level of caspase-3 [18].…”