Human Cancer Genomic Research

Sun City Center, United States

Human Cancer Genomic Research

Sun City Center, United States

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PubMed | Al Faisal University, King Faisal Specialist Hospital And Research Center and Human Cancer Genomic Research
Type: Journal Article | Journal: Carcinogenesis | Year: 2014

The mammalian target of rapamycin (mTOR) signaling cascade is a key regulatory pathway controlling initiation of messenger RNA in mammalian cells. Although dysregulation of mTOR signaling has been reported earlier in cancers, there is paucity of data about mTOR expression in papillary thyroid carcinoma (PTC). Therefore, in this study, we investigated the presence of mTORC2 and mTORC1 complexes in a large cohort of >500 PTC samples. Our clinical data showed the presence of active mTORC1 and mTORC2 in 81 and 39% of PTC samples, respectively. Interestingly, coexpression of mTORC1 and mTORC2 activity was seen in a 32.5% (164/504) of the PTC studied and this association was statistically significant (P = 0.0244). mTOR signaling complex was also found to be associated with activated AKT and 4E-BP1. In vitro, using Torin2, a second-generation mTOR inhibitor or gene silencing of mTOR expression prevented mTORC1 and mTORC2 activity leading to inactivation of P70S6, 4E-BP1, AKT and Bad. Inhibition of mTOR activity led to downregulation of cyclin D1, a gene regulated by messenger RNA translation via phosphorylation of 4E-BP1. Torin2 treatment also inhibited cell viability and induced caspase-dependent apoptosis via activation of mitochondrial apoptotic pathway in PTC cells. Finally, Torin2 treatment induces anticancer effect on PTC xenograft tumor growth in nude mice via inhibition of mTORC1 and mTORC2 and its associated pathways. Our results suggest that coexpression of mTORC1 and mTORC2 is seen frequently in the clinical PTC samples and dual targeting of mTORC1 and mTORC2 activity may be an attractive therapeutic target for treatment of PTC.


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.


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.


PubMed | Human Cancer Genomic Research
Type: | Journal: Molecular medicine (Cambridge, Mass.) | Year: 2012

The Met receptor tyrosine kinase is overexpressed and/or activated in variety of human malignancies. Previously we have shown that c-Met is overexpressed in Middle Eastern papillary thyroid carcinoma (PTC) and significantly associated with an aggressive phenotype, but its role has not been fully elucidated in PTC. The aim of this study was to determine the functional link between the c-Met/AKT signaling pathway and death receptor 5 (DR5) in a large cohort of PTC in a tissue microarray format followed by functional studies using PTC cell lines and nude mice. Our data showed that high expressions of p-Met and DR5 were significantly associated with an aggressive phenotype of PTC and correlated with BRAF mutation. Treatment of PTC cell lines with PHA665752, an inhibitor of c-Met tyrosine kinase, inhibited cell proliferation and induced apoptosis via the mitochondrial pathway in PTC cell lines. PHA665752 treatment or expression of c-Met small interfering (si)RNA resulted in dephosphorylation of c-Met, AKT and its downstream effector molecules. Furthermore, PHA665752 treatment upregulated DR5 expression via generation of reactive oxygen species in PTC cell lines, and synergistically potentiated death receptor-induced apoptosis with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Finally, cotreatment with PHA665752 and TRAIL caused more pronounced effects on PTC xenograft tumor growth in nude mice. Our data suggest that the c-Met/AKT pathway may be a potential target for therapeutic intervention for treatment of PTC refractory to conventionally therapeutic modalities.


PubMed | Human Cancer Genomic Research
Type: Journal Article | Journal: Molecular medicine (Cambridge, Mass.) | 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.

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