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Search Results: 1 - 10 of 134 matches for " Fadlo Khuri "
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Mono- or Double-Site Phosphorylation Distinctly Regulates the Proapoptotic Function of Bax
Qinhong Wang,Shi-Yong Sun,Fadlo Khuri,Walter J. Curran,Xingming Deng
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013393
Abstract: Bax is the major multidomain proapoptotic molecule that is required for apoptosis. It has been reported that phosphorylation of Bax at serine(S) 163 or S184 activates or inactivates its proapoptotic function, respectively. To uncover the mechanism(s) by which phosphorylation regulates the proapoptotic function of Bax, a series of serine (S)→ alanine/glutamate (A/E) Bax mutants, including S163A, S184A, S163E, S184E, S163E/S184A (EA), S163A/S184E (AE), S163A/S184A (AA) and S163E/S184E (EE), were created to abrogate or mimic, respectively, either single or double-site phosphorylation. The compound Bax mutants (i.e. EA and AE) can flesh out the functional contribution of individual phosphorylation site(s). WT and each of these Bax mutants were overexpressed in Bax?/? MEF or lung cancer H157 cells and the proapoptotic activities were compared. Intriguingly, expression of any of Bax mutants containing the mutation S→A at S184 (i.e. S184A, EA or AA) represents more potent proapoptotic activity as compared to WT Bax in association with increased 6A7 epitope conformational change, mitochondrial localization/insertion and prolonged half-life. In contrast, all Bax mutants containing the mutation S→E at S184 (i.e. S184E, AE or EE) have a mobility-shift and fail to insert into mitochondrial membranes with decreased protein stability and less apoptotic activity. Unexpectedly, mutation either S→A or S→E at S163 site does not significantly affect the proapoptotic activity of Bax. These findings indicate that S184 but not S163 is the major phosphorylation site for functional regulation of Bax's activity. Therefore, manipulation of the phosphorylation status of Bax at S184 may represent a novel strategy for cancer treatment.
Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of Geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis
Shuzhen Chen, Lei Fu, Shruti M Raja, Ping Yue, Fadlo R Khuri, Shi-Yong Sun
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-23
Abstract: The GGTase I inhibitor GGTI-298 induced apoptosis and augmented tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. GGTI-298 induced DR4 and DR5 expression and reduced c-FLIP levels. Enforced c-FLIP expression or DR5 knockdown attenuated apoptosis induced by GGTI-298 and TRAIL combination. Surprisingly, DR4 knockdown sensitized cancer cells to GGTI298/TRAIL-induced apoptosis. The combination of GGTI-298 and TRAIL was more effective than each single agent in decreasing the levels of IκBα and p-Akt, implying that GGTI298/TRAIL activates NF-κB and inhibits Akt. Interestingly, knockdown of DR5, but not DR4, prevented GGTI298/TRAIL-induced IκBα and p-Akt reduction, suggesting that DR5 mediates reduction of IκBα and p-Akt induced by GGTI298/TRAIL. In contrast, DR4 knockdown further facilitated GGTI298/TRAIL-induced p-Akt reduction.Both DR5 induction and c-FLIP downregulation contribute to GGTI-298-mediated augmentation of TRAIL-induced apoptosis. Moreover, DR4 appears to play an opposite role to DR5 in regulation of GGTI/TRAIL-induced apoptotic signaling.There are two major apoptotic signaling pathways: the intrinsic mitochondria-mediated pathway and the extrinsic death receptor-induced pathway, and these pathways are linked by the truncated proapoptotic protein Bid [1]. The extrinsic apoptotic pathway is negatively regulated primarily by the cellular FLICE-inhibitory protein (c-FLIP), including both long (FLIPL) and short (FLIPS) forms, through inhibition of caspase-8 activation, whereas the intrinsic apoptotic pathway is negatively regulated by multiple proteins including survivin [2]. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to its receptors: death receptor 4 (DR4, also named TRAIL-R1) and death receptor 5 (DR5, also named TRAIL-R2) to activate the extrinsic apoptotic pathway [3]. Recently TRAIL has received much attention because it preferentially induces apoptosis in transforme
Transcriptional Regulation of YWHAZ, the Gene Encoding 14-3-3ζ
Andrea Kasinski, Xueyuan Dong, Fadlo R. Khuri, Jeremy Boss, Haian Fu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093480
Abstract: Aberrant expression of oncogenic 14-3-3 proteins is correlated with poor survival of cancer patients. While the underlying mechanism of the abnormal expression in tumors remains elusive for the six oncogenic 14-3-3 isoforms; the potential involvement of a transcriptional component has been suggested. Unfortunately, little experimental data has been reported to support this hypothesis. In this study we describe the genetic structure of YWHAZ, the gene encoding 14-3-3ζ, including the identification of previously unreported transcript variants. In total, five transcript variants were revealed and their expressions confirmed in a panel of cell lines. Expressed sequence tag (EST) database mining and in vitro rapid-amplification of cDNA ends (RACE) confirmed that one variant, 1c, represents >80% of the expressed transcripts, which is also the most efficiently translated. An analysis of the proximal promoter of this variant revealed a functional Cyclic-AMP Response Element (CRE). Factors that bound to the CRE element were recognized through fractionation and subsequent EMSAs. This analysis identified CREB and ATF-1 as the trans-interacting factors. Cell-based assays confirm that ATF-1, and to a lesser extent CREB, bind the endogenous YWHAZ promoter especially under TNF-α stimulating conditions. In support of a role of ATF-1 in the regulation of YWHAZ, silencing of ATF-1 resulted in a marked reduction in two of the five YWHAZ transcripts. These data suggest a novel mechanism for the transcriptional regulation of a major pro-survival gene, YWHAZ, by ATF-1.
c-FLIP Degradation Mediates Sensitization of Pancreatic Cancer Cells to TRAIL-Induced Apoptosis by the Histone Deacetylase Inhibitor LBH589
John Kauh,Songqing Fan,Mingjing Xia,Ping Yue,Lily Yang,Fadlo R. Khuri,Shi-Yong Sun
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010376
Abstract: Great efforts have been made to develop novel and efficacious therapeutics against pancreatic cancer to improve the treatment outcomes. Tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) is such a therapeutic cytokine with selective killing effect toward malignant cells. However, some human pancreatic cancers are intrinsically resistant to TRAIL-mediated apoptosis or therapy. In this study, we have shown that the histone deacetylase inhibitor LBH589 can synergize with TRAIL to augment apoptosis even in TRAIL-resistant cells. LBH589 decreased c-FLIP levels in every tested cell line and survivin levels in some of the tested cell lines. Enforced expression of ectopic c-FLIP, but not survivin, abolished the cooperative induction of apoptosis by the combination of LBH589 and TRAIL, indicating that c-FLIP downregulation plays a critical role in LBH589 sensitization of pancreatic cancer cells to TRAIL. Moreover, LBH589 decreased c-FLIP stability and the presence of the proteasome inhibitor MG132 prevented c-FLIP from reduction by LBH589. Correspondingly, we detected increased levels of ubiqutinated c-FLIP in LBH589-treated cells. These data thus indicate that LBH589 promotes ubiqutin/proteasome-mediated degradation of c-FLIP, leading to downregulation of c-FLIP. Collectively, LBH589 induces c-FLIP degradation and accordingly sensitizes pancreatic cancer cells to TRAIL-induced apoptosis, highlighting a novel therapeutic regimen against pancreatic cancer.
The Combination of RAD001 and NVP-BEZ235 Exerts Synergistic Anticancer Activity against Non-Small Cell Lung Cancer In Vitro and In Vivo
Cheng-Xiong Xu,Yikun Li,Ping Yue,Taofeek K. Owonikoko,Suresh S. Ramalingam,Fadlo R. Khuri,Shi-Yong Sun
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020899
Abstract: The phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling axis has emerged as a novel target for cancer therapy. Agents that inhibit PI3K, mTOR or both are currently under development. The mTOR allosteric inhibitor, RAD001, and the PI3K/mTOR dual kinase inhibitor, BEZ235, are examples of these agents. We were interested in developing strategies to enhance mTOR-targeted caner therapy. In this study, we found that BEZ235 alone effectively inhibited the growth of rapamycin-resistant cancer cells. Interestingly, the combination of sub-optimal concentrations of RAD001 and BEZ235 exerted synergistic inhibition of the growth of human lung cancer cells along with induction of apoptosis and G1 arrest. Furthermore, the combination was also more effective than either agent alone in inhibiting the growth of lung cancer xenografts in mice. The combination showed enhanced effects on inhibiting mTOR signaling and reducing the expression of c-Myc and cyclin D1. Taken together, our results suggest that the combination of RAD001 and BEZ235 is a novel strategy for cancer therapy.
Analysis of Death Receptor 5 and Caspase-8 Expression in Primary and Metastatic Head and Neck Squamous Cell Carcinoma and Their Prognostic Impact
Heath A. Elrod,Songqing Fan,Susan Muller,Georgia Z. Chen,Lin Pan,Mourad Tighiouart,Dong M. Shin,Fadlo R. Khuri,Shi-Yong Sun
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012178
Abstract: Death receptor 5 (DR5) and caspase-8 are major components in the extrinsic apoptotic pathway. The alterations of the expression of these proteins during the metastasis of head and neck squamous cell carcinoma (HNSCC) and their prognostic impact have not been reported. The present study analyzes the expression of DR5 and caspase-8 by immunohistochemistry (IHC) in primary and metastatic HNSCCs and their impact on patient survival. Tumor samples in this study included 100 primary HNSCC with no evidence of metastasis, 100 primary HNSCC with lymph node metastasis (LNM) and 100 matching LNM. IHC analysis revealed a significant loss or downregulation of DR5 expression in primary tumors with metastasis and their matching LNM compared to primary tumors with no evidence of metastasis. A similar trend was observed in caspase-8 expression although it was not statistically significant. Downregulation of caspase-8 and DR5 expression was significantly correlated with poorly differentiated tumors compared to moderately and well differentiated tumors. Univariate analysis indicates that, in HNSCC with no metastasis, higher expression of caspase-8 significantly correlated with better disease-free survival and overall survival. However, in HNSCC with LNM, higher caspase-8 expression significantly correlated with poorer disease-free survival and overall survival. Similar results were also generated when we combined both DR5 and caspase-8. Taken together, we suggest that both DR5 and caspase-8 are involved in regulation of HNSCC metastasis. Our findings warrant further investigation on the dual role of caspase-8 in cancer development.
Statistical learning methods as a preprocessing step for survival analysis: evaluation of concept using lung cancer data
Madhusmita Behera, Erin E Fowler, Taofeek K Owonikoko, Walker H Land, William Mayfield, Zhengjia Chen, Fadlo R Khuri, Suresh S Ramalingam, John J Heine
BioMedical Engineering OnLine , 2011, DOI: 10.1186/1475-925x-10-97
Abstract: A small set of clinical variables (CVs) for stage-1 non-small cell lung cancer patients was used to evaluate an approach for using SL methods as a preprocessing step for survival analysis. A stochastic method of training a probabilistic neural network (PNN) was used with differential evolution (DE) optimization. Survival scores were derived stochastically by combining CVs with the PNN. Patients (n = 151) were dichotomized into favorable (n = 92) and unfavorable (n = 59) survival outcome groups. These PNN derived scores were used with logistic regression (LR) modeling to predict favorable survival outcome and were integrated into the survival analysis (i.e. Kaplan-Meier analysis and Cox regression). The hybrid modeling was compared with the respective modeling using raw CVs. The area under the receiver operating characteristic curve (Az) was used to compare model predictive capability. Odds ratios (ORs) and hazard ratios (HRs) were used to compare disease associations with 95% confidence intervals (CIs).The LR model with the best predictive capability gave Az = 0.703. While controlling for gender and tumor grade, the OR = 0.63 (CI: 0.43, 0.91) per standard deviation (SD) increase in age indicates increasing age confers unfavorable outcome. The hybrid LR model gave Az = 0.778 by combining age and tumor grade with the PNN and controlling for gender. The PNN score and age translate inversely with respect to risk. The OR = 0.27 (CI: 0.14, 0.53) per SD increase in PNN score indicates those patients with decreased score confer unfavorable outcome. The tumor grade adjusted hazard for patients above the median age compared with those below the median was HR = 1.78 (CI: 1.06, 3.02), whereas the hazard for those patients below the median PNN score compared to those above the median was HR = 4.0 (CI: 2.13, 7.14).We have provided preliminary evidence showing that the SL preprocessing may provide benefits in comparison with accepted approaches. The work will require further evalu
Inhibition of STAT3 by Niclosamide Synergizes with Erlotinib against Head and Neck Cancer
Rui Li, Shuo You, Zhongliang Hu, Zhuo G. Chen, Gabriel L. Sica, Fadlo R. Khuri, Walter J. Curran, Dong M. Shin, Xingming Deng
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074670
Abstract: Epidermal growth factor receptor (EGFR) is extensively expressed in head and neck cancer. However, EGFR-targeted therapy has only modest efficacy in head and neck cancer, through mechanisms that are not fully understood. Here, we found that inhibition of EGFR by erlotinib stimulated phosphorylation and activation of STAT3 leading to increased Bcl2/Bcl-XL expression in head and neck cancer cells, which may dampen the therapeutic efficacy of erlotinib against head and neck cancer. Erlotinib-enhanced STAT3 phosphorylation results, at least in part, from suppression of its physiological phosphatase, PTPMeg2. Specific knockdown of STAT3 by RNA interference significantly sensitized head and neck cancer cells to erlotinib treatment. Pharmacological inhibition of STAT3 by niclosamide not only blocked erlotinib-stimulated STAT3 phosphorylation but also synergistically repressed head and neck cancer growth in vitro and in vivo. Combined inhibition of EGFR and STAT3 by erlotinib and niclosamide more effectively induced apoptosis in tumor tissues without toxicity for normal tissues. Based on our findings, treatment with erlotinib combined with niclosamide may offer an effective therapeutic approach to improve the prognosis of head and neck cancer.
c-Jun NH2-terminal kinase-dependent upregulation of DR5 mediates cooperative induction of apoptosis by perifosine and TRAIL
Lei Fu, Yi-Dan Lin, Heath A Elrod, Ping Yue, Youtake Oh, Bo Li, Hui Tao, Georgia Z Chen, Dong M Shin, Fadlo R Khuri, Shi-Yong Sun
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-315
Abstract: The combination of perifosine and TRAIL was more active than each single agent alone in inducing apoptosis of head and neck squamous cell carcinoma cells and inhibiting the growth of xenografts. Interestingly, perifosine primarily increased cell surface levels of DR5 although it elevated the expression of both DR4 and DR5. Blockade of DR5, but not DR4 upregulation, via small interfering RNA (siRNA) inhibited perifosine/TRAIL-induced apoptosis. Perifosine increased phosphorylated c-Jun NH2-terminal kinase (JNK) and c-Jun levels, which were paralleled with DR4 and DR5 induction. However, only DR5 upregulaiton induced by perifosine could be abrogated by both the JNK inhibitor SP600125 and JNK siRNA. The antioxidants, N-acetylcysteine and glutathione, but not vitamin C or tiron, inhibited perifosine-induced elevation of p-c-Jun, DR4 and DR5. Moreover, no increased production of reactive oxygen species was detected in perifosine-treated cells although reduced levels of intracellular GSH were measured.DR5 induction plays a critical role in mediating perifosine/TRAIL-induced apoptosis. Perifosine induces DR5 expression through a JNK-dependent mechanism independent of reactive oxygen species.Perifosine, the first orally bioavailable alkylphospholipid, has shown antitumor activity in preclinical models and is currently in Phase II clinical trials [1,2]. The mechanisms underlying perifosine-mediated antitumor effects have not been fully elucidated, although it is known to inhibit Akt [3,4] and induce c-Jun NH2-terminal kinase (JNK) activation [5-7]. Perifosine has also been shown to induce p21 expression, leading to cell cycle arrest [8]. In addition, perifosine in combination with other antitumor agents such as the PDK1 inhibitor, UCN-01 [9], histone deacetylase inhibitors [10], and the chemotherapeutic agent etoposide [11] show synergistic antitumor effects.Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL; also called APO-2L), a member of the TNF family,
Biorthogonality condition for axisymmetric stokes flow in spherical geometries
S. A. Khuri
International Journal of Mathematics and Mathematical Sciences , 2000, DOI: 10.1155/s0161171200002891
Abstract: We derive the biorthogonality condition for axisymmetric Stokes flow in a region between two concentric spheres. This biorthogonality condition is a property satisfied by the eigenfunctions and adjoint eigenfunctions, which is needed to compute the coefficients of the eigenfunction expansion solution of the corresponding creeping flow problem.
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