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Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis.

ABSTRACT: The tumor suppressor protein prostate apoptosis response-4 (Par-4), which is secreted by normal cells, selectively induces apoptosis in cancer cells. We identified a 3-arylquinoline derivative, designated Arylquin 1, as a potent Par-4 secretagogue in cell cultures and mice. Mechanistically, Arylquin 1 binds vimentin, displaces Par-4 from vimentin for secretion and triggers the efficient paracrine apoptosis of diverse cancer cells. Thus, targeting vimentin with Par-4 secretagogues efficiently induces paracrine apoptosis of tumor cells.

SUBMITTER: Burikhanov R

PROVIDER: S-EPMC4201913 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis.

Burikhanov Ravshan R Sviripa Vitaliy M VM Hebbar Nikhil N Zhang Wen W Layton W John WJ Hamza Adel A Zhan Chang-Guo CG Watt David S DS Liu Chunming C Rangnekar Vivek M VM

Nature chemical biology 20140914 11

The tumor suppressor protein prostate apoptosis response-4 (Par-4), which is secreted by normal cells, selectively induces apoptosis in cancer cells. We identified a 3-arylquinoline derivative, designated Arylquin 1, as a potent Par-4 secretagogue in cell cultures and mice. Mechanistically, Arylquin 1 binds vimentin, displaces Par-4 from vimentin for secretion and triggers the efficient paracrine apoptosis of diverse cancer cells. Thus, targeting vimentin with Par-4 secretagogues efficiently ind ...[more]

PMID: 25218743

Similar Datasets

Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin.

Project description:Advanced prostate tumors usually metastasize to the lung, bone, and other vital tissues and are resistant to conventional therapy. Prostate apoptosis response-4 protein (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells by binding specifically to a receptor, Glucose-regulated protein-78 (GRP78), found only on the surface of cancer cells. 3-Arylquinolines or "arylquins" induce normal cells to release Par-4 from the intermediate filament protein, vimentin and promote Par-4 secretion that targets cancer cells in a paracrine manner. A structure-activity study identified arylquins that promote Par-4 secretion, and an evaluation of arylquin binding to the hERG potassium ion channel using a [(3)H]-dofetilide binding assay permitted the identification of structural features that separated this undesired activity from the desired Par-4 secretory activity. A binding study that relied on the natural fluorescence of arylquins and that used the purified rod domain of vimentin (residues 99-411) suggested that the mechanism behind Par-4 release involved arylquin binding to multiple sites in the rod domain.

| S-EPMC4681656 | biostudies-literature

Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis.

Project description:The induction of tumor suppressor proteins capable of cancer cell apoptosis represents an attractive option for the re-purposing of existing drugs. We report that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial. CQ-inducible Par-4 secretion triggers paracrine apoptosis of cancer cells and also inhibits metastatic tumor growth. CQ induces Par-4 secretion via the classical secretory pathway that requires the activation of p53. Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. Our findings indicate that CQ induces p53- and Rab8b-dependent Par-4 secretion from normal cells for Par-4-dependent inhibition of metastatic tumor growth.

| S-EPMC5264245 | biostudies-literature

Par-4 is an essential downstream target of DAP-like kinase (Dlk) in Dlk/Par-4-mediated apoptosis.

Project description:Prostate apoptosis response-4 (Par-4) was initially identified as a gene product up-regulated in prostate cancer cells undergoing apoptosis. In rat fibroblasts, coexpression of Par-4 and its interaction partner DAP-like kinase (Dlk, which is also known as zipper-interacting protein kinase [ZIPK]) induces relocation of the kinase from the nucleus to the actin filament system, followed by extensive myosin light chain (MLC) phosphorylation and induction of apoptosis. Our analyses show that the synergistic proapoptotic effect of Dlk/Par-4 complexes is abrogated when either Dlk/Par-4 interaction or Dlk kinase activity is impaired. In vitro phosphorylation assays employing Dlk and Par-4 phosphorylation mutants carrying alanine substitutions for residues S154, T155, S220, or S249, respectively, identified T155 as the major Par-4 phosphorylation site of Dlk. Coexpression experiments in REF52.2 cells revealed that phosphorylation of Par-4 at T155 by Dlk was essential for apoptosis induction in vivo. In the presence of the Par-4 T155A mutant Dlk was partially recruited to actin filaments but resided mainly in the nucleus. Consequently, apoptosis was not induced in Dlk/Par-4 T155A-expressing cells. In vivo phosphorylation of Par-4 at T155 was demonstrated with a phospho-specific Par-4 antibody. Our results demonstrate that Dlk-mediated phosphorylation of Par-4 at T155 is a crucial event in Dlk/Par-4-induced apoptosis.

| S-EPMC2743620 | biostudies-literature

Cold Atmospheric Plasma and Plasma-Activated Medium Trigger RONS-Based Tumor Cell Apoptosis.

Project description:The selective in vitro anti-tumor mechanisms of cold atmospheric plasma (CAP) and plasma-activated media (PAM) follow a sequential multi-step process. The first step involves the formation of primary singlet oxygen (1O2) through the complex interaction between NO2- and H2O2. 1O2 then inactivates some membrane-associated catalase molecules on at least a few tumor cells. With some molecules of their protective catalase inactivated, these tumor cells allow locally surviving cell-derived, extracellular H2O2 and ONOO─ to form secondary 1O2. These species continue to inactivate catalase on the originally triggered cells and on adjacent cells. At the site of inactivated catalase, cell-generated H2O2 enters the cell via aquaporins, depletes glutathione and thus abrogates the cell's protection towards lipid peroxidation. Optimal inactivation of catalase then allows efficient apoptosis induction through the HOCl signaling pathway that is finalized by lipid peroxidation. An identical CAP exposure did not result in apoptosis for nonmalignant cells. A key conclusion from these experiments is that tumor cell-generated RONS play the major role in inactivating protective catalase, depleting glutathione and establishing apoptosis-inducing RONS signaling. CAP or PAM exposure only trigger this response by initially inactivating a small percentage of protective membrane associated catalase molecules on tumor cells.

| S-EPMC6775051 | biostudies-literature

The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis.

Project description:Prostate apoptosis response-4 (Par-4) is a proapoptotic protein with intracellular functions in the cytoplasm and nucleus. Unexpectedly, we noted Par-4 protein is spontaneously secreted by normal and cancer cells in culture, and by Par-4 transgenic mice that are resistant to spontaneous tumors. Short exposure to endoplasmic reticulum (ER) stress-inducing agents further increased cellular secretion of Par-4 by a brefeldin A-sensitive pathway. Secretion occurred independently of caspase activation and apoptosis. Interestingly, extracellular Par-4 induced apoptosis by binding to the stress response protein, glucose-regulated protein-78 (GRP78), expressed at the surface of cancer cells. The interaction of extracellular Par-4 and cell surface GRP78 led to apoptosis via ER stress and activation of the FADD/caspase-8/caspase-3 pathway. Moreover, apoptosis inducible by TRAIL, which also exerts cancer cell-specific effects, is dependent on extracellular Par-4 signaling via cell surface GRP78. Thus, Par-4 activates an extrinsic pathway involving cell surface GRP78 receptor for induction of apoptosis.

| S-EPMC2774252 | biostudies-literature

Prostate Apoptosis Response-4 (Par-4): A Novel Target in Pyronaridine-Induced Apoptosis in Glioblastoma (GBM) Cells.

Project description:Glioblastoma (GBM) is an aggressive form of brain tumor with a median survival of approximately 12 months. With no new drugs in the last few decades and limited success in clinics for known therapies, drug repurposing is an attractive choice for its treatment. Here, we examined the efficacy of pyronaridine (PYR), an anti-malarial drug in GBM cells. PYR induced anti-proliferative activity in GBM cells with IC50 ranging from 1.16 to 6.82 µM. Synergistic activity was observed when PYR was combined with Doxorubicin and Ritonavir. Mechanistically, PYR triggered mitochondrial membrane depolarization and enhanced the ROS levels causing caspase-3 mediated apoptosis. PYR significantly decreased markers associated with proliferation, EMT, hypoxia, and stemness and upregulated the expression of E-cadherin. Interestingly, PYR induced the expression of intracellular as well as secretory Par-4, a tumor suppressor in GBM cells, which was confirmed using siRNA. Notably, Par-4 levels in plasma samples of GBM patients were significantly lower than normal healthy volunteers. Thus, our study demonstrates for the first time that PYR can be repurposed against GBM with a novel mechanism of action involving Par-4. Herewith, we discuss the role of upregulated Par-4 in a highly interconnected signaling network thereby advocating its importance as a therapeutic target.

| S-EPMC9264948 | biostudies-literature

A trigger model of apoptosis induced by tumor necrosis factor signaling.

Project description:BACKGROUND: The ability of living cells to respond appropriately to apoptosis signals is crucial for the proper development and homeostasis of multicellular organisms. For example, viable cells must be stable enough to appropriately respond to apoptosis signaling so that an irreversible death program is only induced when apoptosis signaling reaches a certain threshold. Previous studies have introduced bistability models in which signaling by caspase-3 activity represents a key regulator of cell fate in response to apoptosis stimuli. RESULTS: In this study, apoptosis induced by tumor necrosis factor (TNF) signaling is investigated, and a mathematical model without the requirement for bistability is proposed. In this model, rapid degradation of the active forms of caspases -8 and -3 are included, and TNF-signaling is found to induce a pulse of caspase-3 activation and trigger an irreversible death program. This result agrees with experimental observations. The ability of a cell to respond to, or resist, apoptosis stimuli is also discussed. Furthermore, the activation efficiencies of caspases -8 and -3 that are essential to a cell's response to extracellular apoptosis stimuli are defined. Based on the simulations performed, it is observed that activation efficiencies must be sufficiently sensitive to appropriately compromise a cell's resistance and effectiveness in response to apoptosis stimuli. CONCLUSIONS: Our results suggest that bistability may not be a necessary condition for the induction of apoptosis by TNF signaling. Rather, a sharp increase in caspase-3 activity might be sufficient to trigger the induction of an irreversible death program. Accordingly, regulation of caspase activity and degradation of active caspases is essential for a cell's response to apoptosis stimuli.

| S-EPMC3121113 | biostudies-literature

Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos).

Project description:The mitochondrial protein apoptosis-inducing factor (AIF) plays a pivotal role in poly(ADP-ribose) polymerase-1 (PARP-1)-mediated cell death (parthanatos), during which it is released from the mitochondria and translocates to the nucleus. We show that AIF is a high-affinity poly(ADP-ribose) (PAR)-binding protein and that PAR binding to AIF is required for parthanatos both in vitro and in vivo. AIF bound PAR at a site distinct from AIF's DNA binding site, and this interaction triggered AIF release from the cytosolic side of the mitochondrial outer membrane. Mutation of the PAR binding site in AIF did not affect its NADH (reduced form of nicotinamide adenine dinucleotide) oxidase activity, its ability to bind FAD (flavin adenine dinucleotide) or DNA, or its ability to induce nuclear condensation. However, this AIF mutant was not released from mitochondria and did not translocate to the nucleus or mediate cell death after PARP-1 activation. These results suggest a mechanism for PARP-1 to initiate AIF-mediated cell death and indicate that AIF's bioenergetic cell survival-promoting functions are separate from its effects as a mitochondrially derived death effector. Interference with the PAR-AIF interaction or PAR signaling may provide notable opportunities for preventing cell death after activation of PARP-1.

| S-EPMC3086524 | biostudies-literature

Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death.

Project description:Apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase, is released into the cytoplasm to induce cell death in response to poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation. How PARP-1 activation leads to AIF release is not known. Here we identify PAR polymer as a cell death signal that induces release of AIF. PAR polymer induces mitochondrial AIF release and translocation to the nucleus. PAR glycohydrolase, which degrades PAR polymer, prevents PARP-1-dependent AIF release. Cells with reduced levels of AIF are resistant to PARP-1-dependent cell death and PAR polymer cytotoxicity. These results reveal PAR polymer as an AIF-releasing factor that plays important roles in PARP-1-dependent cell death.

| S-EPMC1838748 | biostudies-literature

Extracellular vimentin as a target against SARS-CoV-2 host cell invasion.

Project description:Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. In the case of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) has been identified as a necessary receptor, but not all ACE2-expressing cells are equally infected, suggesting that other extracellular factors are involved in host cell invasion by SARS-CoV-2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens' cellular uptake. Here, we present evidence that extracellular vimentin might act as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry. We demonstrate direct binding between vimentin and SARS-CoV-2 pseudovirus coated with the SARS-CoV-2 spike protein and show that antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cells. Our results suggest new therapeutic strategies for preventing and slowing SARS-CoV-2 infection, focusing on targeting cell host surface vimentin.

| S-EPMC7805437 | biostudies-literature

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