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Cited by 140PI3K/AKT/mTOR signaling in cancerHead and Neck Cancer StudiesMetabolism, Diabetes, and Cancer

Targeting mammalian target of rapamycin by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model

Czerninski, Rakefet, Amornphimoltham, Panomwat, Patel, Vyomesh, Molinolo, Alfredo A., Gutkind, J. Silvio·2009·Cancer Prevention Research
DOI 10.1158/1940-6207.capr-08-0147

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Abstract

The increased molecular understanding of cancerous growth may now afford the opportunity to develop novel therapies targeting specific dysregulated molecular mechanisms contributing to the progression of each cancer type. In this regard, the aberrant activation of Akt/mammalian target of rapamycin (mTOR) pathway is a frequent event in head and neck squamous cell carcinomas (HNSCC), thus representing a potential molecular target for the treatment of HNSCC patients. The ability to translate this emerging body of information into effective therapeutic strategies, however, has been hampered by the limited availability of animal models for oral malignancies. Here, we show that the administration in the drinking water to mice of 4-nitroquinoline-1 oxide, a DNA adduct-forming agent that serves as a surrogate of tobacco exposure, leads to the progressive appearance of preneoplastic and tumoral lesions in the tongue and oral mucosa, with 100% incidence after only 16 weeks of carcinogen exposure. Remarkably, many of these lesions evolve spontaneously into highly malignant SCCs few weeks after 4-nitroquinoline-1 oxide withdrawal. In this model, we have observed that the activation of the Akt-mTOR biochemical route represents an early event, which is already detectable in dysplastic lesions. Furthermore, we show that the inhibition of mTOR by the chronic administration of rapamycin halts the malignant conversion of precancerous lesions and promotes the regression of advanced carcinogen-induced SCCs. Together, these findings support the contribution of the mTOR signaling pathway to HNSCC progression and provide a strong rationale for the early evaluation of mTOR inhibitors as a molecular-targeted strategy for HNSCC chemoprevention and treatment.

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  • Inhibition of mTOR by rapamycin and its derivatives has shown promising antitumoral activity in a variety of experimental models of HNSCC.

    “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 Czerninski et al., 2009

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Authors
Czerninski, R., Amornphimoltham, P., Patel, V., Molinolo, A. A., & Gutkind, J. S.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Cancer Prevention Research
Publisher
American Association for Cancer Research (AACR)
Published
2009-01-01
Volume
2
Issue
1
Pages
27-36
ISSN
  • 1940-6207 (ISSN-L)
  • 1940-6215
DOI
10.1158/1940-6207.capr-08-0147
OpenAlex
W2162692590
Cited by
140
References
45
Citations by year
2026: 1 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 7 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 5 · 2015: 11 · 2014: 10 · 2013: 12 · 2012: 14
FWCI
5.90
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Prevention Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
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
mTOR signaling, rapamycin, head and neck squamous cell carcinoma, oral carcinogenesis, 4-nitroquinoline 1-oxide, chemoprevention, Akt/mTOR signaling, precancerous lesions, tongue cancer, oral mucosa, mTOR inhibitors, targeted therapy
MeSH terms
Animals, Antibiotics, Antineoplastic, Carcinogens, Carcinoma, Squamous Cell, Cell Transformation, Neoplastic, Female, Head and Neck Neoplasms, Immunohistochemistry, Mice, Inbred C57BL, Precancerous Conditions, Protein Kinases, 4-Nitroquinoline-1-oxide, Signal Transduction, Gene Expression, Disease Progression, Sirolimus, Mice, TOR Serine-Threonine Kinases

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