The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index.
Mammalian Target of Rapamycin, a Molecular Target in Squamous Cell Carcinomas of the Head and Neck
Abstract
Emerging knowledge on how the dysregulated function of signaling networks contributes to the malignant growth of squamous cell carcinoma of the head and neck (HNSCC) can now be exploited to identify novel mechanism-based anticancer treatments. In this regard, we have observed that persistent activation of the serine/threonine kinase Akt is a frequent event in HNSCC, and that blockade of its upstream kinase, 3'-phosphoinositide-dependent kinase 1, potently inhibits tumor cell growth. Akt promotes cell proliferation by its ability to coordinate mitogenic signaling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). This kinase, in turn, phosphorylates key eukaryotic translation regulators, including p70-S6 kinase and the eukaryotic translation initiation factor, 4E binding protein 1. Indeed, we show here that aberrant accumulation of the phosphorylated active form of S6, the most downstream target of the Akt-mTOR-p70-S6 kinase pathway, is a frequent event in clinical specimens from patients with HNSCC and their derived cell lines. Of interest, this enhanced level of the phosphorylated active form of S6 was rapidly reduced in HNSCC cell lines and HNSCC xenograft models at clinically relevant doses of rapamycin, which specifically inhibits mTOR. Furthermore, we observed that rapamycin displays a potent antitumor effect in vivo, as it inhibits DNA synthesis and induces the apoptotic death of HNSCC cells, ultimately resulting in tumor regression. These findings identify the Akt-mTOR pathway as a potential therapeutic target for HNSCC, and may provide the rationale for the early clinical evaluation of rapamycin and its analogues in patients with HNSCC.
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“Inhibition of mTOR by the use of rapamycin and its derivatives has shown promising antitumoral activity in a variety of experimental models of HNSCC (Amornphimoltham et al., 2008; Amornphimoltham et al., 2005; Czerninski et al., 2009; Nathan et al., 2007)”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Amornphimoltham et al., 2005
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Cites
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Specificity and mechanism of action of some commonly used protein kinase inhibitors
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Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
ERBB receptors and cancer: the complexity of targeted inhibitors
Hynes, N. E., & Lane, H. A. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1609 · Cited by 3,379
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Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Inoki, K., Li, Y., Xu, T., & Guan, K.-L. (2003) · Genes & Development · doi:10.1101/gad.1110003 · Cited by 1,911
Guba, M. O., von Breitenbuch, P., Steinbauer, M. G. M., Koehl, G. E., Flegel, S., Hornung, M., Bruns, C. J., Zuelke, C., Farkas, S. A., Anthuber, M., et al. (2002) · Nature Medicine · doi:10.1038/nm0202-128 · Cited by 1,739
Targeting the PI3K-Akt pathway in human cancer
Luo, J., Manning, B. D., & Cantley, L. C. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00248-4 · Cited by 1,290
Forastiere, A. A., Koch, W. M., Trotti, A., & Sidransky, D. (2001) · New England Journal of Medicine · doi:10.1056/nejmra001375 · Cited by 1,262
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1 of the 63 references couldn’t be matched to a known paper.
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Bhirde, A. A., Patel, V., Gavard, J., Zhang, G., Sousa, A. A., Masedunskas, A., Leapman, R. D., Weigert, R., Gutkind, J. S., & Rusling, J. F. (2009) · ACS Nano · doi:10.1021/nn800551s · Cited by 852
Self-citationDysregulated molecular networks in head and neck carcinogenesis
Molinolo, A., Amornphimoltham, P., SQUARIZE, C. H., CASTILHO, R. M., Patel, V., & Gutkind, J. S. (2008) · Oral Oncology · doi:10.1016/j.oraloncology.2008.07.011 · Cited by 387
Self-citationIglesias-Bartolome, R., Patel, V., Cotrim, A., Leelahavanichkul, K., Molinolo, A. A., Mitchell, J. B., & Gutkind, J. S. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.06.007 · Cited by 284
Self-citationMolinolo, A. A., Hewitt, S. M., Amornphimoltham, P., Keelawat, S., Rangdaeng, S., Meneses García, A., Raimondi, A. R., Jufe, R., Itoiz, M., Gao, Y., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1041 · Cited by 243
Self-citationAlberú, J., Pascoe, M. D., Campistol, J. M., Schena, F. P., Rial, M. D. C., Polinsky, M. S., Neylan, J. F., Korth-Bradley, J. M., Goldberg-Alberts, R., & Maller, E. S. (2011) · Transplantation · doi:10.1097/tp.0b013e3182247ae2 · Cited by 224
Metadata
- Authors
- Amornphimoltham, P., Patel, V., Sodhi, A., Nikitakis, N. G., Sauk, J. J., Sausville, E. A., Molinolo, A. A., & Gutkind, J. S.
- Affiliations
- National Institutes of Health (US)
- University of Maryland, Baltimore (US)
- Venue
- Cancer Research
- Published
- 2005-11-01
- Volume
- 65
- Issue
- 21
- Pages
- 9953-9961
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2115100370
- Cited by
- 238
- References
- 63
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 14 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 10 · 2016: 20 · 2015: 14 · 2014: 14 · 2013: 13 · 2012: 27
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mammalian target of rapamycin, mTOR, head and neck squamous cell carcinoma, Akt signaling, p70 S6 kinase, 4E-binding protein 1, rapamycin, PI3K/AKT/mTOR pathway, translational regulation, apoptosis, cancer therapy, 3-phosphoinositide-dependent kinase 1
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Carcinoma, Squamous Cell, DNA, Neoplasm, Female, Head and Neck Neoplasms, Humans, Mice, Nude, Phosphorylation, Protein Kinases, Signal Transduction, Apoptosis, Phosphatidylinositol 3-Kinases, Sirolimus, Xenograft Model Antitumor Assays, Ribosomal Protein S6 Kinases, 70-kDa, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, Mice, TOR Serine-Threonine Kinases
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