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Preet M Chaudhary - One of the best experts on this subject based on the ideXlab platform.
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Kaposi’s Sarcoma Associated Herpesvirus Encoded Viral FLICE Inhibitory Protein K13 Activates NF-kB Pathway Independent of TRAF6, TAK1 and LUBAC
2016Co-Authors: Hittu Matta, Ramakrishnan Gopalakrishnan, Ciaren Graham, Bhairavi Tolani, Akshat Khanna, Yulan Suo, Preet M ChaudharyAbstract:Background: Kaposi’s sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein (vFLIP) K13 activates the NF-kB pathway by binding to the NEMO/IKKc subunit of the IkB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines. Methodology/Principal Findings: Here we demonstrate that K13-induced NF-kB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpincpdm/cpdm). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-kB activity. K13-induced NF-kB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKa and IKK2/IKKb, which resulted in their activation by ‘‘T Loop’ ’ phosphorylation. Conclusions/Significance: Our results demonstrate that K13 activates the NF-kB pathway by binding to NEMO which results in the recruitment of IKK1/IKKa and IKK2/IKKb and their subsequent activation by phosphorylation. Thus, K13 activates NF
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kaposi s sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein k13 activates nf κb pathway independent of traf6 tak1 and lubac
PLOS ONE, 2012Co-Authors: Hittu Matta, Ramakrishnan Gopalakrishnan, Ciaren Graham, Bhairavi Tolani, Akshat Khanna, Yulan Suo, Preet M ChaudharyAbstract:BACKGROUND: Kaposi's sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein (vFLIP) K13 activates the NF-κB pathway by binding to the NEMO/IKKγ subunit of the IκB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that K13-induced NF-κB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpin(cpdm/cpdm)). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-κB activity. K13-induced NF-κB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKα and IKK2/IKKβ, which resulted in their activation by "T Loop" phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that K13 activates the NF-κB pathway by binding to NEMO which results in the recruitment of IKK1/IKKα and IKK2/IKKβ and their subsequent activation by phosphorylation. Thus, K13 activates NF-κB via a mechanism distinct from that utilized by inflammatory cytokines. These results have important implications for the development of therapeutic agents targeting K13-induced NF-κB for the treatment of KSHV-associated malignancies.
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a20 is induced by kaposi sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein vflip k13 and blocks k13 induced nuclear factor κb in a negative feedback manner
Journal of Biological Chemistry, 2011Co-Authors: Hittu Matta, Vasu Punj, Ramakrishnan Gopalakrishnan, Yulan Suo, Preet M ChaudharyAbstract:Expression of A20, a negative regulator of the NF-κB pathway, is frequently lost in several subtypes of Hodgkin and non-Hodgkin lymphoma. We report that A20 is expressed in Kaposi sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma cell lines, and its expression correlates closely with the expression of KSHV-encoded viral FLICE Inhibitory Protein K13. Ectopic expression of K13 induced A20 expression through NF-κB-mediated activation of A20 promoter. In turn, A20 blocked K13-induced NF-κB activity and up-regulation of proinflammatory cytokines CCL20 and IL-8 in a negative feedback fashion. Both the N-terminal deubiquitinating domain and the C-terminal zinc finger domain of A20 were involved in the inhibition of K13-induced NF-κB activity. Overexpression of A20 blocked K13-induced IκBα phosphorylation, NF-κB nuclear translocation, and cellular transformation. Consistent with the above, K13-induced IκBα phosphorylation and NF-κB transcriptional activation were enhanced in A20-deficient cells. Finally, A20 was found to interact physically with K13. Taken collectively, these results demonstrate that K13 is a key determinant of A20 expression in KSHV-infected cells, and A20 is a key negative regulator of K13-induced NF-κB activity. A20 might serve to control the inflammatory response to KSHV infection and protect KSHV-infected cells from apoptosis.
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kaposi sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein vflip k13 cooperates with myc to promote lymphoma in mice
Cancer Biology & Therapy, 2010Co-Authors: Anwaar Ahmad, Vasu Punj, Hittu Matta, Sandra Schamus, Jason S Groshong, Lisa J Robinson, Parkash S Gill, Preet M ChaudharyAbstract:Primary effusion lymphoma (PEL) is an aggressive form of lymphoma that is associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV). One of the KSHV genes expressed in PEL cells is K13, a potent activator of the NF-κB pathway. K13 transgenic mice develop lymphomas, but after a long period of latency. A possible candidate that could cooperate with K13 in the development of PEL is c-Myc, whose expression is frequently dysregulated in PEL cells. To study the cooperative interaction between K13 and c-Myc in the pathogenesis of PEL, we crossed the K13 transgenic mice to iMycEμ transgenic mice that overexpress Myc. We report that lymphomas in the K13/iMycEμ double transgenic mice developed with shorter latency and were histologically distinct from those observed in the iMycEμ mice. Lymphomas in the K13/iMycEμ mice also lacked the expression of B- and T-cell markers, thus resembling the immunophenotype of PEL. The accelerated development of lymphoma in the K13/iMycEμ mice was associated with in...
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kaposi s sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein vflip k13 suppresses cxcr4 expression by upregulating mir 146a
Oncogene, 2010Co-Authors: Vasu Punj, Hittu Matta, Sandra Schamus, Aletheia Tamewitz, Bean N Anyang, Preet M ChaudharyAbstract:Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)-encoded viral FLICE Inhibitory Protein (vFLIP) K13 is a potent activator of the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we show that infection with KHSV and ectopic expression of K13, but not its NF-kappaB-defective mutant, suppressed the expression of CXCR4. Suppression of CXCR4 by KSHV and K13 was associated with upregulated expression of miR-146a, a microRNA that is known to bind to the 3'-untranslated region of CXCR4 mRNA. Reporter studies identified two NF-kappaB sites in the promoter of miR-146a that were essential for its activation by K13. Accordingly, ectopic expression of K13, but not its NF-kappaB-defective mutant or other vFLIPs, strongly stimulated the miR-146a promoter activity, which could be blocked by specific genetic and pharmacological inhibitors of the NF-kappaB pathway. Finally, expression of CXCR4 was downregulated in clinical samples of KS and this was accompanied by an increased expression of miR-146a. Our results show that K13-induced NF-kappaB activity suppresses CXCR4 through upregulation of miR-146a. Downregulation of CXCR4 expression by K13 may contribute to KS development by promoting premature release of KSHV-infected endothelial progenitors into the circulation.
Yon Rojanasakul - One of the best experts on this subject based on the ideXlab platform.
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FLICE-Inhibitory Protein
2016Co-Authors: Liying Wang, Ubonthip Nimmannitjj, Yon RojanasakulAbstract:Chronic exposure to single-walled carbon nanotubes (SWCNT) has been reported to induce apoptosis resistance of human lung epithelial cells. As resistance to apoptosis is a foundation of neoplastic transformation and cancer development, we evaluated the apoptosis resistance characteristic of the exposed lung cells to understand the pathogenesis mechanism. Passage control and SWCNT-transformed human lung epithelial cells were treated with known inducers of apoptosis via the intrinsic (antimycin A and CDDP) or extrinsic (FasL and TNF-a) pathway and analyzed for apoptosis by DNA fragmentation, annexin-V expression, and caspase activation assays. Whole-genome microarray was performed to aid the analysis of apoptotic gene signaling network. The SWCNT-transformed cells exhibited defective death receptor pathway in association with cellular FLICE-Inhibitory Protein (c-FLIP) overexpression. Knockdown or chemical inhibition of c-FLIP abrogated the apoptosis resistance of SWCNT-transformed cells. Whole-genome expression signature analysis confirmed these findings. This study is the first to demonstrate carbon nanotube-induced defective death receptor pathway and the role of c-FLIP in the process. Key words: carbon nanotubes; lung; apoptosis; c-FLIP; death receptor Carbon nanotubes (CNT) have increasingly being used in the areas of electronics, computers, bioengineering, and drug deliv
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*Department of Pharmaceutical Sciences and
2016Co-Authors: Sudjit Luanpitpong, Liying Wang, Yon Rojanasakul, Todd A Stueckle, Ubonthip Nimmannit, Mary Babb R, Prof Yon RojanasakulAbstract:Carbon nanotubes induce apoptosis resistance of human lung epithelial cells through FLICE-Inhibitory Protein Varisa Pongrakhananon
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carbon nanotubes induce apoptosis resistance of human lung epithelial cells through FLICE Inhibitory Protein
Toxicological Sciences, 2015Co-Authors: Varisa Pongrakhananon, Liying Wang, Sudjit Luanpitpong, Todd A Stueckle, Ubonthip Nimmannit, Yon RojanasakulAbstract:Chronic exposure to single-walled carbon nanotubes (SWCNT) has been reported to induce apoptosis resistance of human lung epithelial cells. As resistance to apoptosis is a foundation of neoplastic transformation and cancer development, we evaluated the apoptosis resistance characteristic of the exposed lung cells to understand the pathogenesis mechanism. Passage control and SWCNT-transformed human lung epithelial cells were treated with known inducers of apoptosis via the intrinsic (antimycin A and CDDP) or extrinsic (FasL and TNF-α) pathway and analyzed for apoptosis by DNA fragmentation, annexin-V expression, and caspase activation assays. Whole-genome microarray was performed to aid the analysis of apoptotic gene signaling network. The SWCNT-transformed cells exhibited defective death receptor pathway in association with cellular FLICE-Inhibitory Protein (c-FLIP) overexpression. Knockdown or chemical inhibition of c-FLIP abrogated the apoptosis resistance of SWCNT-transformed cells. Whole-genome expression signature analysis confirmed these findings. This study is the first to demonstrate carbon nanotube-induced defective death receptor pathway and the role of c-FLIP in the process.
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s nitrosylation of FLICE Inhibitory Protein determines its interaction with rip1 and activation of nf κb
Cell Cycle, 2014Co-Authors: Siera Jo Talbott, Liying Wang, Sudjit Luanpitpong, Neelam Azad, Christian Stehlik, Anand Krishnan V Iyer, Yon RojanasakulAbstract:Death receptor (DR) ligation can lead to divergent signaling pathways causing either caspase-mediated cell death or cell proliferation and inflammation. These variations in cellular fate are determined by adaptor Proteins that are recruited to the DR signaling complex. FLICE Inhibitory Protein (FLIP) is an established inhibitor of caspase-8-mediated apoptosis, and it is also involved in NF-κB activation. However, the molecular mechanism that regulates FLIP within this complex is unknown. In this study, we provide new evidence for the regulation of NF-κB by FLIP through S-nitrosylation, which involves covalent modification of the Protein’s cysteine thiol by nitric oxide to form S-nitrosothiol. Point mutations of FLIP at cysteine residues 254 and 259 prevent FLIP S-nitrosylation and its ability to activate NF-κB. The mechanism by which FLIP nitrosylation regulates NF-κB activity involves RIP1 binding and redistribution, whereas TRAF2 binding and distribution are unaffected. We further show that FLIP processing and cleavage is dependent on its nitrosylation status. Collectively, our study reveals a novel pathway for FLIP regulation of NF-κB through Protein S-nitrosylation, which is a key posttranslational mechanism controlling DR-mediated cell death and survival. Since increased expression of FLIP and nitric oxide are frequently observed in chemotherapy-resistant tumors, S-nitrosylation of FLIP could be a key mechanism of chemoresistance and tumor growth.
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Dependence of Reactive Oxygen Species and FLICE Inhibitory Protein on Lipofectamine-Induced Apoptosis in Human Lung Epithelial Cells
The Journal of pharmacology and experimental therapeutics, 2008Co-Authors: Lalana Kongkaneramit, Liying Wang, Neelam Azad, Anand Krishnan V Iyer, Narong Sarisuta, Yon RojanasakulAbstract:Cationic liposomes such as Lipofectamine (LF) are widely used as nonviral gene delivery vectors; however, their clinical application is limited by their cytotoxicity. These agents have been shown to induce apoptosis as the primary mode of cell death, but their mechanism of action is not well understood. The present study investigated the mechanism of LF-induced apoptosis and examined the role of reactive oxygen species (ROS) in this process. We found that LF induced apoptosis of human epithelial H460 cells through a mechanism that involves caspase activation and ROS generation. Inhibition of caspase activity by pan-caspase inhibitor (z-VAD-fmk) or by specific caspase-8 inhibitor (z-IETD-fmk) or caspase-9 inhibitor (z-LEHD-fmk) inhibited the apoptotic effect of LF. Overexpression of FLICE-Inhibitory Protein (FLIP) or B-cell lymphoma-2, which are known inhibitors of the extrinsic and intrinsic death pathways, respectively, similarly inhibited apoptosis by LF. Induction of apoptosis by LF was shown to require ROS generation because its inhibition by ROS scavengers or by ectopic expression of antioxidant enzyme superoxide dismutase and glutathione peroxidase strongly inhibited the apoptotic effect of LF. Electron spin resonance studies showed that LF induced multiple ROS; however, superoxide was found to be the primary ROS responsible for LF-induced apoptosis. The mechanism by which ROS mediate the apoptotic effect of LF involves down-regulation of FLIP through the ubiquitination pathway. In demonstrating the role of FLIP and ROS in LF death signaling, we document a novel mechanism of apoptosis regulation that may be exploited to decrease cytotoxicity and increase gene transfection efficiency of cationic liposomes.
Hittu Matta - One of the best experts on this subject based on the ideXlab platform.
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Kaposi’s Sarcoma Associated Herpesvirus Encoded Viral FLICE Inhibitory Protein K13 Activates NF-kB Pathway Independent of TRAF6, TAK1 and LUBAC
2016Co-Authors: Hittu Matta, Ramakrishnan Gopalakrishnan, Ciaren Graham, Bhairavi Tolani, Akshat Khanna, Yulan Suo, Preet M ChaudharyAbstract:Background: Kaposi’s sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein (vFLIP) K13 activates the NF-kB pathway by binding to the NEMO/IKKc subunit of the IkB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines. Methodology/Principal Findings: Here we demonstrate that K13-induced NF-kB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpincpdm/cpdm). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-kB activity. K13-induced NF-kB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKa and IKK2/IKKb, which resulted in their activation by ‘‘T Loop’ ’ phosphorylation. Conclusions/Significance: Our results demonstrate that K13 activates the NF-kB pathway by binding to NEMO which results in the recruitment of IKK1/IKKa and IKK2/IKKb and their subsequent activation by phosphorylation. Thus, K13 activates NF
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kaposi s sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein k13 activates nf κb pathway independent of traf6 tak1 and lubac
PLOS ONE, 2012Co-Authors: Hittu Matta, Ramakrishnan Gopalakrishnan, Ciaren Graham, Bhairavi Tolani, Akshat Khanna, Yulan Suo, Preet M ChaudharyAbstract:BACKGROUND: Kaposi's sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein (vFLIP) K13 activates the NF-κB pathway by binding to the NEMO/IKKγ subunit of the IκB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that K13-induced NF-κB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpin(cpdm/cpdm)). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-κB activity. K13-induced NF-κB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKα and IKK2/IKKβ, which resulted in their activation by "T Loop" phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that K13 activates the NF-κB pathway by binding to NEMO which results in the recruitment of IKK1/IKKα and IKK2/IKKβ and their subsequent activation by phosphorylation. Thus, K13 activates NF-κB via a mechanism distinct from that utilized by inflammatory cytokines. These results have important implications for the development of therapeutic agents targeting K13-induced NF-κB for the treatment of KSHV-associated malignancies.
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a20 is induced by kaposi sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein vflip k13 and blocks k13 induced nuclear factor κb in a negative feedback manner
Journal of Biological Chemistry, 2011Co-Authors: Hittu Matta, Vasu Punj, Ramakrishnan Gopalakrishnan, Yulan Suo, Preet M ChaudharyAbstract:Expression of A20, a negative regulator of the NF-κB pathway, is frequently lost in several subtypes of Hodgkin and non-Hodgkin lymphoma. We report that A20 is expressed in Kaposi sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma cell lines, and its expression correlates closely with the expression of KSHV-encoded viral FLICE Inhibitory Protein K13. Ectopic expression of K13 induced A20 expression through NF-κB-mediated activation of A20 promoter. In turn, A20 blocked K13-induced NF-κB activity and up-regulation of proinflammatory cytokines CCL20 and IL-8 in a negative feedback fashion. Both the N-terminal deubiquitinating domain and the C-terminal zinc finger domain of A20 were involved in the inhibition of K13-induced NF-κB activity. Overexpression of A20 blocked K13-induced IκBα phosphorylation, NF-κB nuclear translocation, and cellular transformation. Consistent with the above, K13-induced IκBα phosphorylation and NF-κB transcriptional activation were enhanced in A20-deficient cells. Finally, A20 was found to interact physically with K13. Taken collectively, these results demonstrate that K13 is a key determinant of A20 expression in KSHV-infected cells, and A20 is a key negative regulator of K13-induced NF-κB activity. A20 might serve to control the inflammatory response to KSHV infection and protect KSHV-infected cells from apoptosis.
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kaposi sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein vflip k13 cooperates with myc to promote lymphoma in mice
Cancer Biology & Therapy, 2010Co-Authors: Anwaar Ahmad, Vasu Punj, Hittu Matta, Sandra Schamus, Jason S Groshong, Lisa J Robinson, Parkash S Gill, Preet M ChaudharyAbstract:Primary effusion lymphoma (PEL) is an aggressive form of lymphoma that is associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV). One of the KSHV genes expressed in PEL cells is K13, a potent activator of the NF-κB pathway. K13 transgenic mice develop lymphomas, but after a long period of latency. A possible candidate that could cooperate with K13 in the development of PEL is c-Myc, whose expression is frequently dysregulated in PEL cells. To study the cooperative interaction between K13 and c-Myc in the pathogenesis of PEL, we crossed the K13 transgenic mice to iMycEμ transgenic mice that overexpress Myc. We report that lymphomas in the K13/iMycEμ double transgenic mice developed with shorter latency and were histologically distinct from those observed in the iMycEμ mice. Lymphomas in the K13/iMycEμ mice also lacked the expression of B- and T-cell markers, thus resembling the immunophenotype of PEL. The accelerated development of lymphoma in the K13/iMycEμ mice was associated with in...
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kaposi s sarcoma associated herpesvirus encoded viral FLICE Inhibitory Protein vflip k13 suppresses cxcr4 expression by upregulating mir 146a
Oncogene, 2010Co-Authors: Vasu Punj, Hittu Matta, Sandra Schamus, Aletheia Tamewitz, Bean N Anyang, Preet M ChaudharyAbstract:Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)-encoded viral FLICE Inhibitory Protein (vFLIP) K13 is a potent activator of the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we show that infection with KHSV and ectopic expression of K13, but not its NF-kappaB-defective mutant, suppressed the expression of CXCR4. Suppression of CXCR4 by KSHV and K13 was associated with upregulated expression of miR-146a, a microRNA that is known to bind to the 3'-untranslated region of CXCR4 mRNA. Reporter studies identified two NF-kappaB sites in the promoter of miR-146a that were essential for its activation by K13. Accordingly, ectopic expression of K13, but not its NF-kappaB-defective mutant or other vFLIPs, strongly stimulated the miR-146a promoter activity, which could be blocked by specific genetic and pharmacological inhibitors of the NF-kappaB pathway. Finally, expression of CXCR4 was downregulated in clinical samples of KS and this was accompanied by an increased expression of miR-146a. Our results show that K13-induced NF-kappaB activity suppresses CXCR4 through upregulation of miR-146a. Downregulation of CXCR4 expression by K13 may contribute to KS development by promoting premature release of KSHV-infected endothelial progenitors into the circulation.
Shiyong Sun - One of the best experts on this subject based on the ideXlab platform.
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the natural product honokiol preferentially inhibits cellular FLICE Inhibitory Protein and augments death receptor induced apoptosis
Molecular Cancer Therapeutics, 2008Co-Authors: Shruti M Raja, Ping Yue, Fadlo R Khuri, Shuzhen Chen, Timothy M Acker, Benjamin Lefkove, Jack L Arbiser, Shiyong SunAbstract:Targeting death receptor-mediated apoptosis has emerged as an effective strategy for cancer therapy. However, certain types of cancer cells are intrinsically resistant to death receptor-mediated apoptosis. In an effort to identify agents that can sensitize cancer cells to death receptor-induced apoptosis, we have identified honokiol, a natural product with anticancer activity, as shown in various preclinical studies, as an effective sensitizer of death receptor-mediated apoptosis. Honokiol alone moderately inhibited the growth of human lung cancer cells; however, when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), greater effects on decreasing cell survival and inducing apoptosis than TRAIL alone were observed, indicating that honokiol cooperates with TRAIL to enhance apoptosis. This was also true to Fas-induced apoptosis when combined with Fas ligand or an agonistic anti-Fas antibody. Among several apoptosis-associated Proteins tested, cellular FLICE-Inhibitory Protein (c-FLIP) was the only one that was rapidly down-regulated by honokiol in all of the tested cell lines. The down-regulation of c-FLIP by honokiol could be prevented by the proteasome inhibitor MG132. Moreover, honokiol increased c-FLIP ubiquitination. These results indicate that honokiol down-regulates c-FLIP by facilitating its degradation through a ubiquitin/proteasome-mediated mechanism. Enforced expression of ectopic c-FLIP abolished the ability of honokiol to enhance TRAIL-induced apoptosis. Several honokiol derivatives, which exhibited more potent effects on down-regulation of c-FLIP than honokiol, showed better efficacy than honokiol in inhibiting the growth and enhancing TRAIL-induced apoptosis as well. Collectively, we conclude that c-FLIP down-regulation is a key event for honokiol to modulate the death receptor-induced apoptosis.
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ccaat enhancer binding Protein homologous Protein dependent death receptor 5 induction and ubiquitin proteasome mediated cellular FLICE Inhibitory Protein down regulation contribute to enhancement of tumor necrosis factor related apoptosis inducing ligand induced apoptosis by dimethyl celecoxib in human non small cell lung cancer cells
Molecular Pharmacology, 2007Co-Authors: Shuzhen Chen, Xiangguo Liu, Ping Yue, Axel H Schonthal, Fadlo R Khuri, Shiyong SunAbstract:2,5-Dimethyl-celecoxib (DMC) is a derivative of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor with anticancer activity in both preclinical studies and clinical practice, and lacks COX-2-Inhibitory activity. Several preclinical studies have demonstrated that DMC has better apoptosis-inducing activity than celecoxib, albeit with undefined mechanisms, and exhibits anticancer activity in animal models. In this study, we primarily investigated DMC9s cooperative effect with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the induction of apoptosis and the underlying mechanisms in human non–small-cell lung cancer (NSCLC) cells. We found that DMC was more potent than celecoxib in decreasing the survival and inducing apoptosis of NSCLC cells. When combined with TRAIL, DMC exerted enhanced or synergistic effects on the induction of apoptosis, indicating that DMC cooperates with TRAIL to augment the induction of apoptosis. To determine the underlying mechanism of the synergy between DMC and TRAIL, we have demonstrated that DMC induces a CCAAT/enhancer binding Protein homologous Protein-dependent expression of DR5, a major TRAIL receptor, and reduces the levels of cellular FLICE-Inhibitory Protein (c-FLIP) (both the long and short forms), key inhibitors of death receptor-mediated apoptosis, by facilitating c-FLIP degradation through a ubiquitin/proteasome-dependent mechanism. It is noteworthy that enforced expression of c-FLIP or silencing of DR5 expression using DR5 small interfering RNA abrogated the enhanced effects on induction of apoptosis by the combination of DMC and TRAIL, indicating that both DR5 up-regulation and c-FLIP reduction contribute to cooperative induction of apoptosis by the combination of DMC and TRAIL. Together, we conclude that DMC sensitizes human NSCLC cells to TRAIL-induced apoptosis via induction of DR5 and down-regulation of c-FLIP.
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cellular FLICE Inhibitory Protein down regulation contributes to celecoxib induced apoptosis in human lung cancer cells
Cancer Research, 2006Co-Authors: Xiangguo Liu, Ping Yue, Axel H Schonthal, Fadlo R Khuri, Shiyong SunAbstract:The cyclooxygenase-2 (COX-2) inhibitor celecoxib is an approved drug in the clinic for colon cancer chemoprevention and has been tested for its chemopreventive and therapeutic efficacy in various clinical trials. Celecoxib induces apoptosis in a variety of human cancer cells including lung cancer cells. Our previous work has shown that celecoxib induces death receptor 5 expression, resulting in induction of apoptosis and enhancement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. In the current study, we further show that celecoxib down-regulated the expression of cellular FLICE-Inhibitory Protein (c-FLIP), a major negative regulator of the death receptor-mediated extrinsic apoptotic pathway, through a ubiquitin/proteasome-dependent mechanism independent of COX-2 in human lung cancer cells. Overexpression of c-FLIP, particularly FLIP(L), inhibited not only celecoxib-induced apoptosis but also apoptosis induced by the combination of celecoxib and TRAIL. These results thus indicate that c-FLIP down-regulation also contributes to celecoxib-induced apoptosis and enhancement of TRAIL-induced apoptosis, which complements our previous finding that the extrinsic apoptotic pathway plays a critical role in celecoxib-induced apoptosis in human lung cancer cells. Collectively, we conclude that celecoxib induces apoptosis in human lung cancer cells through activation of the extrinsic apoptotic pathway, primarily by induction of death receptor 5 and down-regulation of c-FLIP.
Xiangguo Liu - One of the best experts on this subject based on the ideXlab platform.
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down regulation of cellular FLICE Inhibitory Protein long form contributes to apoptosis induced by hsp90 inhibition in human lung cancer cells
Cancer Cell International, 2012Co-Authors: Qilin Wang, Xuexi Hao, Wendong Sun, Xiangguo LiuAbstract:Background Cellular FLICE-Inhibitory Protein (long form, c-FLIPL) is a critical negative regulator of death receptor-mediated apoptosis. Overexpression of c-FLIPL has been reported in many cancer cell lines and is associated with chemoresistance. In contrast, down-regulation of c-FLIP may drive cancer cells into cellular apoptosis. This study aims to demonstrate that inhibition of the heat shock Protein 90 (Hsp90) either by inhibitors geldanamycin/17-N-Allylamino-17-demethoxygeldanamycin (GA/17-AAG) or siRNA technique in human lung cancer cells induces c-FLIPL degradation and cellular apoptosis through C-terminus of Hsp70-interacting Protein (CHIP)-mediated mechanisms.
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Death Receptor 5 and cellular FLICE-Inhibitory Protein regulate pemetrexed-induced apoptosis in human lung cancer cells
European Journal of Cancer, 2011Co-Authors: Guangbo Liu, Xuexi Hao, Ning Zhong, Diansheng Zhong, Xiangguo Liu, Sunil SinghalAbstract:Pemetrexed is a clinically available anti-folate therapeutic agent used in combination with cisplatin for the management of patients with malignant pleural mesothelioma and advanced non-small cell lung cancer. Pemetrexed inhibits three enzymes in purine and pyrimidine synthesis necessary for precursor DNA nucleotides which in turn disrupts growth and survival of normal and cancer cells. The mechanism by which pemetrexed induces apoptosis remains largely uncharacterised. In the current study, we examined the downstream effect of pemetrexed in inducing apoptosis in lung cancer cells. We showed that pemetrexed induced apoptosis via up-regulation of Death Receptor 5 (DR5), an important death receptor for tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). In addition, we discovered a synergistic effect of combination pemetrexed and recombinant TRAIL in inducing apoptosis. Modulating DR5 induction by small interfering RNA abrogated the ability of pemetrexed to induce apoptosis. In addition, silencing of C/EBP homologous Protein (CHOP) expression reduced DR5 expression, demonstrating that the transcriptional factor CHOP has a pivotal role on DR5 up-regulation following pemetrexed treatment. In addition, enforced expression of cellular FLICE-Inhibitory Protein (c-FLIP), a known inhibitor of caspase 8, protected neoplastic cells from apoptosis despite pemetrexed and/or TRAIL therapy. Thus, our findings demonstrate the efficacy and mechanistic underpinnings of pemetrexed-induced apoptosis, and they suggest pemetrexed may have clinical utility when used in combination with TRAIL for the management of patients with lung cancer.
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ccaat enhancer binding Protein homologous Protein dependent death receptor 5 induction and ubiquitin proteasome mediated cellular FLICE Inhibitory Protein down regulation contribute to enhancement of tumor necrosis factor related apoptosis inducing ligand induced apoptosis by dimethyl celecoxib in human non small cell lung cancer cells
Molecular Pharmacology, 2007Co-Authors: Shuzhen Chen, Xiangguo Liu, Ping Yue, Axel H Schonthal, Fadlo R Khuri, Shiyong SunAbstract:2,5-Dimethyl-celecoxib (DMC) is a derivative of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor with anticancer activity in both preclinical studies and clinical practice, and lacks COX-2-Inhibitory activity. Several preclinical studies have demonstrated that DMC has better apoptosis-inducing activity than celecoxib, albeit with undefined mechanisms, and exhibits anticancer activity in animal models. In this study, we primarily investigated DMC9s cooperative effect with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the induction of apoptosis and the underlying mechanisms in human non–small-cell lung cancer (NSCLC) cells. We found that DMC was more potent than celecoxib in decreasing the survival and inducing apoptosis of NSCLC cells. When combined with TRAIL, DMC exerted enhanced or synergistic effects on the induction of apoptosis, indicating that DMC cooperates with TRAIL to augment the induction of apoptosis. To determine the underlying mechanism of the synergy between DMC and TRAIL, we have demonstrated that DMC induces a CCAAT/enhancer binding Protein homologous Protein-dependent expression of DR5, a major TRAIL receptor, and reduces the levels of cellular FLICE-Inhibitory Protein (c-FLIP) (both the long and short forms), key inhibitors of death receptor-mediated apoptosis, by facilitating c-FLIP degradation through a ubiquitin/proteasome-dependent mechanism. It is noteworthy that enforced expression of c-FLIP or silencing of DR5 expression using DR5 small interfering RNA abrogated the enhanced effects on induction of apoptosis by the combination of DMC and TRAIL, indicating that both DR5 up-regulation and c-FLIP reduction contribute to cooperative induction of apoptosis by the combination of DMC and TRAIL. Together, we conclude that DMC sensitizes human NSCLC cells to TRAIL-induced apoptosis via induction of DR5 and down-regulation of c-FLIP.
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cellular FLICE Inhibitory Protein down regulation contributes to celecoxib induced apoptosis in human lung cancer cells
Cancer Research, 2006Co-Authors: Xiangguo Liu, Ping Yue, Axel H Schonthal, Fadlo R Khuri, Shiyong SunAbstract:The cyclooxygenase-2 (COX-2) inhibitor celecoxib is an approved drug in the clinic for colon cancer chemoprevention and has been tested for its chemopreventive and therapeutic efficacy in various clinical trials. Celecoxib induces apoptosis in a variety of human cancer cells including lung cancer cells. Our previous work has shown that celecoxib induces death receptor 5 expression, resulting in induction of apoptosis and enhancement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. In the current study, we further show that celecoxib down-regulated the expression of cellular FLICE-Inhibitory Protein (c-FLIP), a major negative regulator of the death receptor-mediated extrinsic apoptotic pathway, through a ubiquitin/proteasome-dependent mechanism independent of COX-2 in human lung cancer cells. Overexpression of c-FLIP, particularly FLIP(L), inhibited not only celecoxib-induced apoptosis but also apoptosis induced by the combination of celecoxib and TRAIL. These results thus indicate that c-FLIP down-regulation also contributes to celecoxib-induced apoptosis and enhancement of TRAIL-induced apoptosis, which complements our previous finding that the extrinsic apoptotic pathway plays a critical role in celecoxib-induced apoptosis in human lung cancer cells. Collectively, we conclude that celecoxib induces apoptosis in human lung cancer cells through activation of the extrinsic apoptotic pathway, primarily by induction of death receptor 5 and down-regulation of c-FLIP.