Overexpressed eIF4E Is Functionally Active in Surgical Margins of Head and Neck Cancer Patients via Activation of the Akt/Mammalian Target of Rapamycin Pathway

Nathan, Cherie‐Ann O.; Amirghahari, Nazanin; Abreo, Fleurette; Rong, Xiaohua; Caldito, Gloria; Jones, M; Zhou, Huijuan; Smith, Melanie; Donnellan, Kimberly; Glass, Jonathan

doi:10.1158/1078-0432.ccr-03-0483

Cited by 97 publications

(89 citation statements)

References 46 publications

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“…PI3K-initiated pathway is the most frequently altered in HNSCC (43) and activation of Akt is shown to be a frequent event in HNSCC (44). Overexpression of eIF4E with the activation of Akt/mTOR pathway was also noted in the surgical margins of HNSCC (45). Activation of Akt was constantly associated with disease progression in different types of cancer (35,41,44).…”

Section: Discussionmentioning

confidence: 99%

Increased NBS1 Expression Is a Marker of Aggressive Head and Neck Cancer and Overexpression of NBS1 Contributes to Transformation

Yang¹,

Chiang²,

Chou³

et al. 2006

Clinical Cancer Research

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Purpose: Head and neck squamous cell carcinoma (HNSCC) represents the sixth most frequent type of cancer worldwide. However, the molecular genetic alterations underlying its malignant behavior and progression are little known. We showed previously that c-MYC directly activates the expression of the DNA double-strand break repair gene NBS1, and NBS1overexpression contributes to transformation. Here, we investigate the role of NBS1overexpression in HNSCC. Experimental Design: Immunohistochemistry analysis of NBS1 expression was done in 81 locally advanced HNSCC patients. Real-time PCR andWestern blot analysis were used to confirm immunohistochemistry results. Human hypopharyngeal cancer cell lines (FADU) with overexpressing NBS1 (FADUNBS) or inducible short interference RNA to repress endogenous NBS1 (FADUNBSi) were generated by stable transfection. Soft agar clonogenicity assay was used to determine the transformation activity. Western blot analysis and phosphatidylinositol 3-kinase (PI3K) assay were done to evaluate the signaling pathways that were involved. Results: NBS1 overexpression was identified in 45% of advanced HNSCC patients. It was an independent marker of poor prognosis. NBS1expression levels correlated with the transformation activity of FADU clones and also correlated with the phosphorylation levels of Akt and its downstream target mammalian target of rapamycin (mTOR). PI3K activity was increased in NBS1-overexpressing FADU clones. NBS1 overexpression also correlated with increased Akt phosphorylation levels in tumor samples. Conclusions: Increased NBS1expression is a significant prognostic marker of advanced HNSCC, and the underlying mechanism may involve the activation of the PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 99%

Increased NBS1 Expression Is a Marker of Aggressive Head and Neck Cancer and Overexpression of NBS1 Contributes to Transformation

Yang¹,

Chiang²,

Chou³

et al. 2006

Clinical Cancer Research

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“…Activation of the mTOR pathway specifically increased phosphorylation of its downstream target p70s6k. Therefore, the level of phosphorylated p70s6k and its substrate rps6 can be used to index mTOR activity (Nathan et al, 2004;Martin et al, 2007). Phosphorylated p70s6k further activates rps6 and possibly the translation initiation factor eIF4B, leading to initiation of 5ЈTOP mRNA translation (van der Velden and Thomas, 1999; Meyuhas, 2000; Raught et al, 2004;Ruvinsky and Meyuhas, 2006).…”

Section: Discussionmentioning

confidence: 99%

Nucleus Accumbens Core Mammalian Target of Rapamycin Signaling Pathway Is Critical for Cue-Induced Reinstatement of Cocaine Seeking in Rats

Wang¹,

Luo²,

He³

et al. 2010

J. Neurosci.

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Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth and survival by controlling translation in response to nutrients and growth factors, has been demonstrated to be involved in neuronal adaptations that underlie drug addiction and learning and memory. We investigated the potential role of the mTOR signaling pathway in relapse to cocaine seeking by using the cue-induced reinstatement model in self-administering rats. We found that exposure to a cocaine-related cue induced reinstatement to cocaine seeking and increased phosphorylation of p70s6 kinase (p70s6k) and ribosomal protein s6 (rps6), measures of mTOR activity, in the nucleus accumbens (NAc) core but not shell. Furthermore, inhibition of NAc core but not shell p70s6k and rps6 phosphorylation by rapamycin decreased cue-induced reinstatement of cocaine seeking. Finally, stimulation of NAc core p70s6k and rps6 phosphorylation by NMDA enhanced cue-induced reinstatement, an effect reversed by rapamycin pretreatment. Additionally, rapamycin infusion into the NAc core or shell did not alter ongoing cocaine self-administration or cue-induced reinstatement of sucrose seeking. These findings indicate that cue-induced reinstatement of cocaine seeking is mediated by activation of the mTOR signaling pathway in the NAc core.

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“…Signaling pathways upstream and downstream of MTOR appear dysregulated in greater than 90% of HNSCC (8) and we have shown overexpression of EIF4E in tumor-free surgical margins is an independent predictor of recurrence (9) and is activated by the AKT/ MTOR pathway (10). In earlier studies, as the degree of dysplasia increased, there was an increase in EIF4E overexpression in surgical margins of HNSCC patients (11).…”

Section: Introductionmentioning

confidence: 59%

“…Soluble proteins extracted from cell lines and tumor cells from the in vivo experiments in the established tumor model were analyzed by Western blot (10). The following antibodies were used: rabbit polycolonal primary antibodies from Cell Signaling: 4E binding protein 1 (4EBP1; 1:500), phospho-4EBP1 (Thr37/46; p-4EBP1; 1:250), S6 ribosomal protein (1:100), phospho-S6 ribosomal protein (Ser235/236; 1:100), AKT (1:250), phospho-AKT (Ser473; 1:250), caspase-3 (1:1,000), MMP-9 (1:500 dilution), and actin (1:3,500).…”

Section: Western Blot Analysis Of Treated Cells and Tumorsmentioning

confidence: 99%

Curcumin Inhibits Carcinogen and Nicotine-Induced Mammalian Target of Rapamycin Pathway Activation in Head and Neck Squamous Cell Carcinoma

Clark

McEachern

Shah

et al. 2010

Cancer Prevention Research

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Curcumin appears to be a safe, bioactive food compound that is a potential chemopreventive for patients at a high risk for head and neck squamous cell carcinoma (HNSCC). Identification and validation of intermediate endpoints is an important step in evaluating chemopreventive agents. AKT/ MTOR pathway biomarkers are intrinsic to the carcinogenic process as well as the mechanism of intervention with curcumin. Antiproliferative effects of curcumin were assayed in 9 HNSCC and a keratinocyte cell line. Nicotine, a genotoxic alkaloid involved in tobacco addiction, forms DNA adducts and has been implicated in upper aerodigestive tract cancer promotion. The antiproliferative effects of curcumin were associated with inhibition of the AKT/MTOR pathway in presence and absence of nicotine, which also induced this pathway. Curcumin was highly effective at suppressing growth of SCC40 xenografts and its activity is associated with modulation of MTOR's downstream target pS6. Curcumin at 15 mg significantly increased survival (286 AE 37 vs. 350 days) in the 4NQO carcinogenic model survival study. A major cause of lethal progression of HNSCC is local regional migration and invasion of malignant cells, and curcumin significantly inhibited cancer cell migration and invasion in vitro and in vivo where downregulation of pS6 was associated with a significant decrease in MMP-9. This is the first study to demonstrate that curcumin inhibits the adverse effects of nicotine by blocking nicotine-induced activation of the AKT/MTOR pathway in HNSCC, which retards cell migration. These studies indicate that inhibiting the AKT/MTOR pathway with curcumin may be useful as an oral chemopreventive agent. Cancer Prev Res; 3(12); 1586-95. Ó2010 AACR.

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Overexpressed eIF4E Is Functionally Active in Surgical Margins of Head and Neck Cancer Patients via Activation of the Akt/Mammalian Target of Rapamycin Pathway

Cited by 97 publications

References 46 publications

Increased NBS1 Expression Is a Marker of Aggressive Head and Neck Cancer and Overexpression of NBS1 Contributes to Transformation

Increased NBS1 Expression Is a Marker of Aggressive Head and Neck Cancer and Overexpression of NBS1 Contributes to Transformation

Nucleus Accumbens Core Mammalian Target of Rapamycin Signaling Pathway Is Critical for Cue-Induced Reinstatement of Cocaine Seeking in Rats

Curcumin Inhibits Carcinogen and Nicotine-Induced Mammalian Target of Rapamycin Pathway Activation in Head and Neck Squamous Cell Carcinoma

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