Roya Khosravi-Far

Harvard University | Harvard · Pathology

Once activated, some surface receptors promote membrane movements that open new portals of endocytosis, in part to facilitate the internalization of their activated complexes. The prototypic death receptor Fas (CD95/Apo1) promotes a wave of enhanced endocytosis that induces a transient intermixing of endosomes with mitochondria in cells that requir...

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification. Experimental design: Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5...

s: AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA Background: Pancreatic ductal adenocarcinoma (PDAC) is a truly devastating disease, primarily due to late diagnosis when curative resection is no longer possible and the lack of accurate early detection biomarkers. Therefore, in...

Recombinant soluble TRAIL and agonistic antibodies against TRAIL receptors (DR4 and DR5) are currently being created for clinical cancer therapy, due to their selective killing of cancer cells and high safety characteristics. However, resistance to TRAIL and other targeted therapies is an important issue facing current cancer research field. An att...

BACKGROUND: Our previous report showed that phosphorylated-survivin at Ser81 induces survivin back loop to activate protein kinase A (PKA) in the cytoprotection mechanism. Activated PKA could possibly induce the cytoprotection via Phosphatydilinositol 3-kinase (PI3K). Therefore our current study was conducted to investigate the possibility of survi...

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Largely due to late diagnosis when curative resection is no longer possible, Pancreatic Adenocarcinoma (PDAC) is a devastating disease marked by a mortality rate nearly equivalent to its incidence rate. While serum CA19-9 is associated with PDAC, it lacks the sensiti...

FOXO family members (FOXOs: FOXO1, FOXO3, FOXO4 and FOXO6) are important transcription factors and tumor suppressors controlling cell homeostasis and cell fate. They are characterized by an extraordinary functional diversity, being involved in regulation of cell cycle, proliferation, apoptosis, DNA damage response, oxidative detoxification, cell di...

Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAF(V600E) have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner...

One of the objectives in the development of effective cancer therapy is induction of tumor-selective cell death. Toward this end, we have identified a small peptide that, when introduced into cells via a TAT cell-delivery system, shows a remarkably potent cytoxicity in a variety of cancer cell lines and inhibits tumor growth in vivo, whereas sparin...

Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens...

Successful translation of findings derived from preclinical studies into effective therapies is critical in biomedical research. Lack of robustness and reproducibility of the preclinical data, due to insufficient number of repeats, inadequate cell-based and mouse models contribute to the poor success rate. Antibodies are widely used in preclinical...

FOXO transcription factors, as regulators of a variety of cellular functions, including promotion of apoptotic cell death, are negatively regulated by various oncogenic signaling cascades and have emerged as bona fide tumor suppressors. Indeed, studies by others and us have shown that the suppression of FOXO function is critical in promoting evasio...

Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAF V600E have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner...

Brought to you by the editorial team of Cell Death and Differentiation, Cell Death and Disease is a peer-reviewed author-pays online journal in the field of translational cell death. It seeks to promote diverse and integrated areas of Experimental and Internal Medicine with its specialties, including Cancer, Immunity and Neuroscience.

BACKGROUND: Survivin, a bifunctional protein, acts as suppressor of apoptosis and has an essential role in mitosis. Survivin is physically phosphorylated on Thr34, and other important sites such as Thr117, Ser20, Thr48 and Ser81. Our previous report has shown that Ser81 of survivin plays role in cytoprotection. In order to investigate the underlyin...

BCR-ABL is a key mediator in the pathogenesis of all cases of chronic myelogenous leukemia (CML) and a subset of precursor B-acute lymphoblastic leukemia (Ph+ALL). Previous animal and cell-based studies have shown that the expression of members of the Forkhead family of tumor suppressors, including FoxO3, is suppressed in BCR-ABL-expressing cells....

CD36 plays a critical role in the inhibition of angiogenesis through binding to the type 1 repeats of thrombospondin-1 (TSP-1) and activating Fyn tyrosine kinase and MAPK pathways. Here, we reveal a novel association of CD36 with VEGFR-2 and spleen tyrosine kinase (Syk). We also address the correlation between the expression of CD36 and Syk by demo...

The promotion of cellular survival, dedifferentiation, and uncontrolled proliferation via the suppression of apoptotic effectors is a fundamental characteristic of tumor cells. As substrates that are negatively regulated by oncogenic signaling cascades driven by AKT, SGK (serum- and glucocorticoid-inducible kinase), IkB kinase (IKK), ERK, and cycli...

Apoptosis is a tightly regulated cell suicide program that plays an essential role in the development and maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Impairment of this native defense mechanism promotes aberrant cellular proliferation and the accumulation of genetic defects, ultimately resulting in tumorigenesis,...

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Bcr-Abl fusion protein plays a critical role in the pathogenesis and progression of Chronic Myelogenous Leukemia (CML) and in some of the Acute Lymphocytic Leukemia (ALL) cases. Current inhibitors of Abl kinases, such as Imatinib, have shown great promise in the treatmen...

BACKGROUND: Survivin is rarely expressed in normal healthy adult tissues, however, it is upregulated in the majority of cancers. Survivin, which belongs to IAPs family, has been widely reported to protect cells from apoptosis by inhibiting caspases pathway. Survivin’s mitotic activity is modulated by many kinases, and its phosphor status can also i...

BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). Although ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of B...

The cellular factors inhibiting apoptosis are often employed by cancer cells to resist therapy. c-FLIP is an endogenous inhibitor of apoptosis upregulated in many drug resistant tumors. Herein, we show that a peptide derived from c-FLIP is a potent inducer of apoptosis in both in vitro and in vivo cancer models. Mechanistic studies suggest that the...

Forkhead box transcription factor FOXO3a, a key regulator of cell survival, is regulated by reversible phosphorylation and subcellular localization. Although the kinases regulating FOXO3a activity have been characterized, the role of protein phosphatases (PP) in the control of FOXO3a subcellular localization and function is unknown. In this study,...

Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competi...

BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). Although ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of B...

As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of ang...

The death receptor Fas/CD95 initiates apoptosis by engaging diverse cellular organelles including endosomes. The link between Fas signaling and membrane traffic has remained unclear, in part because it may differ in diverse cell types. After a systematic investigation of all known pathways of endocytosis, we have clarified that Fas activation opens...

Participation of diverse organelles in the intracellular signalling that follows CD95/Fas receptor ligation encompasses a series of subcellular changes that are mandatory for, or even bolster, the apoptotic cascade. In the present study, we analysed the role of endocytosis in the propagation of cell death signalling after CD95/Fas engagement in typ...

Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) initiate pathways of cell death in which caspase activation is mediated either directly (without mitochondrial amplification), or indirectly via the release of apoptogenic factors from mitochondria. Phospholipid scramblases (PLS) are enzymes that play a key role in cellular funct...

Apoptosis is a tightly regulated cell suicide program that plays an essential role in the maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Defects in this native defense mechanism promote malignant transformation and frequently confer chemoresistance to transformed cells. Indeed, the evasion of apoptosis has been recog...

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines. TRAIL has gained much attention because of its ability to preferentially kill tumor cells with no apparent toxic side effects. Recently, different TRAIL receptor agonists, including TRAIL itself and various agonistic monoclonal antibodi...

Mitochondria have long been known to be critical for cell survival due to their role in energy metabolism. However, not until the mid-1990s did it become evident that mitochondria are also active participants in programmed cell death (PCD). This chapter focuses mainly on the role the mitochondria in mammalian cell death and cancer progression and t...

Apoptosis is a cell suicide program that plays a critical role in development and tissue homeostasis. The ability of cancer cells to evade this programmed cell death (PCD) is a major characteristic that enables their uncontrolled growth. The efficiency of chemotherapy in killing such cells depends on the successful induction of apoptosis, since def...

For more than 100 years scientists have fervently sought the fundamental origins of tumorigenesis, with the ultimate hope of discovering a cure. Indeed, these efforts have led to a significant understanding that multiple genetic and molecular aberrations, such as increased proliferation and the inhibition of apoptosis, contribute to the canonical c...

Numerous studies have revealed that the BCR-ABL oncoprotein abnormally engages a multitude of signaling pathways, some of which may be important for its leukemogenic properties. Central to this has been the determination that the tyrosine kinase function of BCR-ABL is mainly responsible for its transforming potential, and can be targeted with small...

Introduction Chapter 1: Cell Death: History and Future by Zahra Zakeri and Richard A. Lockshin Chapter 2: Caspase Mechanisms by Guy S. Salvesen and Stefan J. Riedl Chapter 3: The Mitochondrial Death Pathway by Anas Chalah and Roya Khosravi-Far Chapter 4: Apoptotic Pathways in Tumor Progression and Therapy by Armelle Melet, Keli Song, Octavian Bucur...

A fundamental characteristic of cancer cells is suppression of apoptosis and increased cell survival.1,2 These properties, when combined with deregulated cell proliferation, are the basic requirements for development of cancer. Increased deregulated cell proliferation by itself paradoxically may trigger cell death pathways which prevent outgrowth o...

The p53 pathway is targeted for inactivation in most human cancers either directly or indirectly, highlighting its critical function as a tumor suppressor gene. p53 is normally activated by cellular stress and mediates a growth-suppressive response that involves cell cycle arrest and apoptosis. In the case of cell cycle arrest, p21 appears sufficie...

A mechanism for circumventing apoptosis prevalent in many cancer cells is the overexpression of antiapoptotic BCL-2 family members. Upregulated expression of BCL-2 may be required to permit ongoing death signaling without a cellular response. Therefore, antagonizing BCL-2 function may cause death in many cancer cells. The selection for expression o...

The Ubiquitin-proteasome pathway (UPP) regulates normal intracellular protein degradation processes essential for cell cycle progression, inflammation, transcription, DNA replication, and apoptosis. Blockade of UPP using proteasome inhibitor Bortezomib (Velcade) is an effective therapy for relapsed/refractory multiple myeloma (MM). Both oligonucleo...

Cell death was observed and understood since the 19th century, but there was no experimental examination until the mid-20th century. Beginning in the 1960s, several laboratories demonstrated that cell death was biologically controlled (programmed) and that the morphology was common and not readily explained (apoptosis). By 1990, the genetic basis o...

The Rel/NF-κB transcription factors are key regulators of programmed cell death (PCD). Their activity has significant physiological relevance for normal development and homeostasis in various tissues and important pathological consequences are associated with aberrant NF-κB activity, including hepatocyte apoptosis, neurodegeneration, and cancer. Wh...

Epigenic modifications, mainly DNA methylation and acetylation, are recognized as the main mechanisms contributing to the malignant phenotype. Acetylation and deacetylation are catalyzed by specific enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. While histones represent a primary target for the physiologi...

The endogenous RNA interference (RNAi) pathway regulates cellular differentiation and development using small noncoding hairpin RNAs, called microRNAs. This chapter will review the link between mammalian microRNAs and genes involved in cellular proliferation, differentiation, and apoptosis. Some microRNAs act as oncogenes or tumor suppressor genes,...

Autophagy is a process by which the cell recycles its components through self-consumption of cellular organelles and bulk cytoplasm. In times of stress, it serves to generate much needed nutrients. When overactivated, however, the orderly destruction of organelles can lead to cell death. At times, autophagic cell death is used as an alternative to...

PI-3K/Akt is Involved in NRP-1-mediated HUVEC survival. a. PI3K is involved in NRP-1-mediated EC survival signaling. Apoptosis assay was performed in HUVEC transfected with EGNP-1 or co-transfected with EGNP-1 with p85(DN) and stimulated with or without 10 ng/ml EGF for 48 hours, and then treated with LY294002 for 39 minutes, accordingly. (i) HUVEC...

GIPC is involved in NRP-1-mediated EC survival. a. GIPC is involved in NRP-1-mediated HUVEC survival. TUNEL assay was performed in HUVEC transfected with EGNP-1 and then transfected with siRNA, and stimulated with or without 10 ng/ml GEF for 48 hours. (i) HUVEC/5%FBS. (ii) HUVEC/0.1% FBS. (iii) HUVEC/EGNP-1/0.1% FBS/EGF. (iv) HUVEC/EGNP-1/0.03pM GI...

p53 inactivation in NRP-1-mediated EC survival. a. Determination of the quantity of apoptotic EC nuclei in zebrafish embryos (n>30). Fluorescent image of embryos injected with indicated morpholinos and subjected to the antibody stain with anti-GFP antibody and TUNEL assay to detect apoptosis. i. Control; ii. zNRP-1a/1b MOs (4.5 ng+4.5 ng); iii. zNR...

NRP-1 mediates VPF/VEGF-induced EC survival. NRP-1 mediates VPF/VEGFinduced PAEC survival. TUNEL assay was performed in PAEC or PAEC/NRP-1 stimulated with or withour 10 ng/ml VPF/VEGF for 48 hours. (i) PAEC/5%FBS. (ii) PAEC/0.1% FBS. (iii) PAEC/0.1% FBS/VEGF; (iv) PAEC/NRP-1/5%FBS; (v) PAEC/NRP-1/0.1% FBS; (vi)PAEC/NRP-1/0.1%FBS/VEGF. b. EGNP-1 med...

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resista...

We have identified a novel pro-apoptotic p53 target gene named CDIP (Cell Death Involved p53-target). Inhibition of CDIP abrogates p53-mediated apoptotic responses, demonstrating that CDIP is an important p53 apoptotic effector. CDIP itself potently induces apoptosis that is associated with caspase-8 cleavage, implicating the extrinsic cell death p...

Subcellular organelles such as mitochondria, endoplasmic reticulum (ER) and the Golgi complex are involved in the progression of the cell death programme. We report here that soon after ligation of Fas (CD95/Apo1) in type II cells, elements of the Golgi complex intermix with mitochondria. This mixing follows centrifugal dispersal of secretory membr...

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), one of the crucial pro-angiogenic factors, functions as a potent inhibitor of endothelial cell (EC) apoptosis. Previous progress has been made towards delineating the VPF/VEGF survival signaling downstream of the activation of VEGFR-2. Here, we seek to define the function o...

Extracellular signal-regulated protein kinase (ERK) 5 is a mitogen-activated protein kinase (MAPK) that is activated by dual phosphorylation via a unique MAPK/ERK kinase 5, MEK5. The physiological importance of this signaling cascade is underscored by the early embryonic death caused by the targeted deletion of the erk5 or the mek5 genes in mice. H...

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines and has been shown to induce cell death in many types of tumor and transformed cells but not in normal cells. This tumor-selective property has made TRAIL a promising candidate for the development of cancer therapy. However, safety issue...

Angiogenesis plays a critical role in the growth and metastasis of tumors. Thrombospondin-1 (TSP-1) is a potent angiogenesis inhibitor, and down-regulation of TSP-1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. Expression of TSP-1 is up-regulated by the tumor suppressor gene, p53, and down-regulate...

Commentary to: Expression of Osteopontin and HGF/Met in Adult Soft Tumors Vivien H.C. Bramwell, Alan B. Tuck, Sylvia M. Wilson, Larry W. Stitt, Anil K. Cherian, Stewart, C. Rorke, Walleed Al-Katib, Carl O. Postenka, Ann F. Chambers Vol: 4 | Issue: 12 | pgs: 1336-1341