Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells.

Different studies have reported that inhibiting the mevalonate pathway with statins may increase the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although the signaling mechanism leading to this sensitization remains largely unknown. We investigated the role of the YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex in the metabolic control of TRAIL sensitivity by the mevalonate pathway. We show that depleting nuclear YAP/TAZ in tumor cells, either via treatment with statins or by silencing YAP/TAZ expression with siRNAs, facilitates the activation of apoptosis by TRAIL.

Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.

Oncogenic transformation leads to changes in glutamine metabolism that make transformed cells highly dependent on glutamine for anabolic growth and survival. Herein, we investigated the cell death mechanism activated in glutamine-addicted tumor cells in response to the limitation of glutamine metabolism. We show that glutamine starvation triggers a FADD and caspase-8-dependent and mitochondria-operated apoptotic program in tumor cells that involves the pro-apoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), but is independent of its cognate ligand TRAIL.

Restoring TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer.

The uncontrolled proliferation of malignant cells in growing tumors results in the generation of different stressors in the tumor microenvironment, such as nutrient shortage, hypoxia and acidosis, among others, that disrupt endoplasmic reticulum (ER) homeostasis and may lead to ER stress. As a response to ER stress, both normal and tumor cells launch a set of signaling pathways known as the unfolded protein response (UPR) to restore ER proteostasis and maintain cell viability and function. However, under sustained ER stress, an apoptotic cell death process can be induced and this has been the subject of different review articles, although the role of the TRAIL-R2/DR5-activated extrinsic pathway of apoptosis has not yet been thoroughly summarized.

cFLIP downregulation is an early event required for endoplasmic reticulum stress-induced apoptosis in tumor cells.

Protein misfolding or unfolding and the resulting endoplasmic reticulum (ER) stress frequently occur in highly proliferative tumors. How tumor cells escape cell death by apoptosis after chronic ER stress remains poorly understood. We have investigated in both two-dimensional (2D) cultures and multicellular tumor spheroids (MCTSs) the role of caspase-8 inhibitor cFLIP as a regulator of the balance between apoptosis and survival in colon cancer cells undergoing ER stress.

Caspase-8 modulates physiological and pathological angiogenesis during retina development.

During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates cell death via both apoptosis and necroptosis.

PIM kinases mediate resistance of glioblastoma cells to TRAIL by a p62/SQSTM1-dependent mechanism.

Glioblastoma (GBM) is the most common and aggressive brain tumor and is associated with poor prognosis. GBM cells are frequently resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and finding new combinatorial therapies to sensitize glioma cells to TRAIL remains an important challenge. PIM kinases are serine/threonine kinases that promote cell survival and proliferation and are highly expressed in different tumors.

Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition.

Apoptosis is a highly regulated form of programmed cell death, essential to the development and homeostasis of multicellular organisms. Cytochrome c is a central figure in the activation of the apoptotic intrinsic pathway, thereby activating the caspase cascade through its interaction with Apaf-1. Our recent studies have revealed 14-3-3ε (a direct inhibitor of Apaf-1) as a cytosolic cytochrome c target.

Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.

Glutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast cancers (TNBC) are highly metastatic and associated with poor prognosis. TNBC cells show a marked dependence on extracellular glutamine for growth.

Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells.

Recent evidences indicate that triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype show a basal activation of the unfolded protein response (UPR) that increases their sensitivity to endoplasmic reticulum (ER) stress although the underlying cell death mechanism remains largely unexplored. Here we show that both caspase-8-dependent and -independent apoptotic mechanisms are activated in TNBC cells undergoing sustained ER stress. Activation of the extrinsic apoptotic pathway by ER stress involves ATF4-dependent upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5).

Oncogenic p95HER2/611CTF primes human breast epithelial cells for metabolic stress-induced down-regulation of FLIP and activation of TRAIL-R/Caspase-8-dependent apoptosis.

Oncogenic transformation triggers reprogramming of cell metabolism, as part of the tumorigenic process. However, metabolic reprogramming may also increase the sensitivity of transformed cells to microenvironmental stress, at the early stages of tumor development. Herein, we show that transformation of human breast epithelial cells by the p95HER2/611CTF oncogene markedly sensitizes these cells to metabolic stress induced by the simultaneous inhibition of glucose and glutamine metabolism.

Autophagy requires poly(adp-ribosyl)ation-dependent AMPK nuclear export.

AMPK is a central energy sensor linking extracellular milieu fluctuations with the autophagic machinery. In the current study we uncover that Poly(ADP-ribosyl)ation (PARylation), a post-translational modification (PTM) of proteins, accounts for the spatial and temporal regulation of autophagy by modulating AMPK subcellular localisation and activation. More particularly, we show that the minority AMPK pool needs to be exported to the cytosol in a PARylation-dependent manner for optimal induction of autophagy, including ULK1 phosphorylation and mTORC1 inactivation.

Opposing roles of TGF-β and EGF in the regulation of TRAIL-induced apoptosis in human breast epithelial cells.

Transforming growth factor-beta (TGF-β) induces the epithelial to mesenchymal transition (EMT) in breast epithelial cells and plays an important role in mammary morphogenesis and breast cancer. In non-transformed breast epithelial cells TGF-β antagonizes epidermal growth factor (EGF) action and induces growth inhibition. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to participate in lumen formation during morphogenesis of human breast epithelial cells.

Structural basis for inhibition of the histone chaperone activity of SET/TAF-Iβ by cytochrome c.

Chromatin is pivotal for regulation of the DNA damage process insofar as it influences access to DNA and serves as a DNA repair docking site. Recent works identify histone chaperones as key regulators of damaged chromatin's transcriptional activity. However, understanding how chaperones are modulated during DNA damage response is still challenging.

Deciphering the insights of poly(ADP-ribosylation) in tumor progression.

Poly (ADP-ribose) polymerase (PARP) inhibitors are particularly efficient against tumors with defects in the homologous recombination repair pathway. Nonetheless poly(ADP-ribosylation) (PARylation) modulates prometastasic activities and adaptation of tumor to a hostile microenvironment. Modulation of metastasis-promoting traits is possible through the alteration of key transcription factors involved in the regulation of the hypoxic response, the recruitment of new vessels (or angiogenesis), and the stimulation of epithelial to mesenchymal transition (EMT).

Activated ERBB2/HER2 licenses sensitivity to apoptosis upon endoplasmic reticulum stress through a PERK-dependent pathway.

HER2/Neu/ERBB2 is a receptor tyrosine kinase overexpressed in approximately 20% of human breast tumors. Truncated or mutant isoforms that show increased oncogenicity compared with the wild-type receptor are found in many breast tumors. Here, we report that constitutively active ERBB2 sensitizes human breast epithelial cells to agents that induce endoplasmic reticulum stress, altering the unfolded protein response (UPR) of these cells.

The long and winding road to cancer treatment: the TRAIL system.

Activation of cell surface death receptors of the tumor necrosis factor (TNF) receptor superfamily by the appropriate ligands represents an attractive therapeutic strategy to induce cell death by apoptosis in cancer cells. However, the toxic effects of TNF-alpha and CD95/Fas ligand (FasL) in normal tissues have significantly hampered the clinical application of these ligands in cancer treatment. TNF-related apoptosis-inducing ligand (TRAIL/APO-2L), another member of the TNF family, has been shown to induce apoptosis selectively in many tumor cell lines.

ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy.

In response to nutrient stress, cells start an autophagy program that can lead to adaptation or death. The mechanisms underlying the signaling from starvation to the initiation of autophagy are not fully understood. In the current study we show that the absence or inactivation of PARP-1 strongly delays starvation-induced autophagy.

ER stress sensitizes cells to TRAIL through down-regulation of FLIP and Mcl-1 and PERK-dependent up-regulation of TRAIL-R2.

Despite recent evidences suggesting that agents inducing endoplasmic reticulum (ER) stress could be exploited as potential antitumor drugs in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the mechanisms of this anticancer action are not fully understood. Moreover, the effects of ER stress and TRAIL in nontransformed cells remain to be investigated. In this study we report that ER stress-inducing agents sensitizes both transformed and nontransformed cells to TRAIL-induced apoptosis.

Itch/AIP4-independent proteasomal degradation of cFLIP induced by the histone deacetylase inhibitor SAHA sensitizes breast tumour cells to TRAIL.

The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) is undergoing clinical trials as an antitumor drug and has received regulatory approval for cancer treatment. Here, we show that pre-treatment of human breast cancer cells with SAHA makes them susceptible to apoptosis induced by TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). The apoptosis of breast tumour cells induced by TRAIL is blocked at the level of apical activation of caspase-8 and SAHA enhances the TRAIL-induced processing of procaspase-8.

Cellular FLIP(L) plays a survival role and regulates morphogenesis in breast epithelial cells.

Strong evidences support the inhibitory activity of cellular FLICE-inhibitory protein (FLIP) in the apoptotic signalling by death receptors in tumor cells. However, little is known about the role of FLIP in the regulation of apoptosis in non-transformed cells. In this report, we demonstrate that FLIP(L) plays an important role as a survival protein in non-transformed breast epithelial cells.

Autophagy inhibition sensitizes multiple myeloma cells to 17-dimethylaminoethylamino-17-demethoxygeldanamycin-induced apoptosis.

The Hsp90 inhibitor 17DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) is currently undergoing clinical trials as an antitumor drug. We show here that treatment of human multiple myeloma (MM) cells with 17DMAG induces mTOR inhibition and microtubule-associated protein light chain 3 (LC3) conversion (LC3-I to LC3-II), an indicator of autophagy. Interestingly, 17DMAG synergistically induces apoptosis through a mitochondria-operated pathway in the presence of the autophagy inhibitor 3-methyladenine (3-MA).

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily member that is being considered as a new strategy in anticancer therapy because of its ability to induce apoptosis, alone or in combination with other stimuli, in many cancer cells. AMP-activated protein kinase (AMPK) is an evolutionarily conserved key regulator of cellular energy homeostasis that protects the cell from energy depletion and stress by activating several biochemical pathways that lead to the conservation, as well as generation, of ATP. Here we report that a number of AMPK activators, including the small molecule activator A-769662, markedly sensitize TRAIL-resistant breast cancer cells to TRAIL-induced apoptosis.

Down-regulation of RIP expression by 17-dimethylaminoethylamino-17-demethoxygeldanamycin promotes TRAIL-induced apoptosis in breast tumor cells.

The Hsp90 inhibitor 17DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) is undergoing clinical trials as an antitumor drug. We show here that treatment of human breast cancer cells with 17DMAG facilitates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Down-regulation of receptor interacting protein (RIP1) is observed upon 17DMAG treatment concomitantly with inhibition of IkappaBalpha phosphorylation.

TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells.

The capacity of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) to trigger apoptosis preferentially in cancer cells, although sparing normal cells, has motivated clinical development of TRAIL receptor agonists as anti-cancer therapeutics. The molecular mechanisms responsible for the differential TRAIL sensitivity of normal and cancer cells are, however, poorly understood. Here, we show a novel signalling pathway that activates cytoprotective autophagy in untransformed human epithelial cells treated with TRAIL.