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Uddin S.,Human Cancer Genomic Research | Jehan Z.,Human Cancer Genomic Research | Ahmed M.,Human Cancer Genomic Research | Alyan A.,Human Cancer Genomic Research | And 4 more authors.
Molecular Medicine | Year: 2011

Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of fatty acids, has been shown to be deregulated in.several cancers, including epithelial ovarian carcinoma (EOC). In this study, we investigated the function of the FASN signaling.pathway in a large series of Middle Eastern EOC patient samples, a panel of cell lines and nude mouse model. Using immunohistochemistry,.we detected overexpression of FASN in 75.5% (114/151) of the tumor samples. Overexpression of FASN was associated.significantly with tumor proliferative marker Ki-67 (P = 0.0009), activated AKT (P = 0.0117) and XIAP (P = 0.0046). Treatment of EOC.cell lines with C-75, a selective inhibitor of FASN, caused inhibition of EOC cell viability via induction of apoptosis. Inhibition of FASN.by C-75 led apoptosis via the mitochondrial pathway. FASN inhibition caused downregulation of activated AKT and its downstream.targets. In addition, inhibition by FASN siRNA caused downregulation of FASN and activation of caspases, suggesting the.role of FASN in C-75 mediated apoptosis. Furthermore, treatment of EOC cells with subtoxic doses of C-75 augmented the effect.of cisplatin-mediated induction of apoptosis. Finally, treatment of EOC cell line xenografts with a combination of C-75 and cisplatin.resulted in growth inhibition of tumors in nude mice through downregulation of FASN and activation of caspases. Altogether,.our results show overexpression of FASN in Middle Eastern EOC, suggesting that FASN may be a potential therapeutic target in a.subset of EOC, alone or in combination with other conventional chemotherapeutic agents. © 2011 The Feinstein Institute for Medical Research.


Bavi P.,Human Cancer Genomic Research | Uddin S.,Human Cancer Genomic Research | Bu R.,Human Cancer Genomic Research | Ahmed M.,Human Cancer Genomic Research | And 7 more authors.
Journal of Pathology | Year: 2011

NF-κB is frequently over-expressed in a variety of non-Hodgkin's lymphomas (NHLs) and has been implicated in lymphomagenesis; however, its role in diffuse large B cell lymphoma (DLBCL) as a prognostic biomarker has not been fully elucidated. Therefore, we investigated the role of NF-κB and its association with clinicopathological features in a tissue microarray cohort of 230 DLBCL patient samples. We then elucidated the role of NF-κB inhibition on cell viability and apoptosis in vitro, using DLBCL cell lines. Using immunohistochemistry, NF-κB was detected in 25.6% (52/203) DLBCL tumours, was associated with activated B cell (ABC) phenotype (p = 0.0054), Epstein-Barr virus (EBV; p = 0.0080) and over-expression of the anti-apoptotic marker XIAP (p = 0.0013). DLBCL cases with nuclear expression of NF-κB showed a significantly poorer overall survival as compared to those without NF-κB expression (p = 0.0236). In a multivariate analysis using a Cox proportional hazard model for IPI and NF-κB expression, the relative risk was 2.97 for high NF-κB expression (95% CI 1.27-6.94; p = 0.0113) and 7.55 for the high-IPI group (95% CI 3.34-18.35; p < 0.0001). In vitro, Bay 11-7085 inhibited constitutively active NF-κB expression in a dose-dependent manner and inhibition of NF-κB also down-regulated expression of the downstream target gene products Bcl-2, Bcl-XL (BCL2L1), XIAP and Survivin, leading to apoptosis via activation of the mitochondrial apoptotic pathway. NF-κB over-expression was found to be an independent prognostic marker for poor survival in DLBCL. Altogether, these results suggest that NF-κB may be a useful prognostic biomarker and a potential target for therapeutic intervention in DLBCL. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Uddin S.,Human Cancer Genomic Research | Hussain A.R.,Human Cancer Genomic Research | Ahmed M.,Human Cancer Genomic Research | Bu R.,Human Cancer Genomic Research | And 5 more authors.
Molecular Cancer Therapeutics | Year: 2010

Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers; however, its role in diffuse large. B-cell lymphoma (DLBCL) has not been fully elucidated. In this study, we investigated the role of FASN in a large series of DLBCL tissues in a tissue microarray (TMA) format followed by in vitro studies using DLBCL cell lines. FASN was found to be expressed in 62.6% DLBCL samples and was seen in highly proliferative tumors, manifested by high Ki67 (P < 0.0001). Significant association was found between tumors expressing high FASN and c-Met tyrosine kinase (P < 0.0002), as well as p-AKT (P = 0.0309). In vitro, pharmacological FASN inhibition and small interference RNA (siRNA) targeted against FASN triggered caspase-dependent apoptosis and suppressed expression of c-Met kinase in DLBCL cell lines, which further highlighted the molecular link between FASN and c-Met kinase. Finally, simultaneous targeting of FASN and c-Met with specific chemical inhibitors induced a synergistically stimulated apoptotic response in DLBCL cell lines. These findings provide evidence that FASN, via c-Met tyrosine kinase, plays a critical role in the carcinogenesis of DLBCL and strongly suggest that targeting FASN may have therapeutic value in treatment of DLBCL. © 2010 American Association for Cancer Research.

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