A Retroinhibition Approach Reveals a Tumor Cell–Autonomous Response to Rapamycin in Head and Neck Cancer

Amornphimoltham, Panomwat; Patel, Vyomesh; Leelahavanichkul, Kantima; Abraham, Robert T.; Gutkind, J. Silvio

doi:10.1158/0008-5472.can-07-1756

Cited by 43 publications

(46 citation statements)

References 46 publications

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“…The anti-proliferative effects in a head and neck squamous cell carcinoma (HNSCC) cell line were induced with a rapamycin micromolar dosage higher than that used in our study (Aissat et al, 2008). In contrast, a recent study revealed that a nanomolar dose of rapamycin did not have an anti-proliferative effect on HNSCC cell lines in vitro, but did induce apoptosis of cancer cells in vivo by the anti-angiogenic effects of rapamycin (Amornphimoltham et al, 2008).…”

Section: Discussionmentioning

confidence: 77%

Pharmacological Retention of Oral Mucosa Progenitor/Stem Cells

et al. 2009

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Oral mucosa progenitor/stem cells reside as a small-sized cell population that eventually differentiates concurrently with an increase in cell size. Activation of the mammalian target of rapamycin (mTOR) leads to an increase in cell size. We hypothesized that rapamycin, a specific inhibitor of mTOR, will maintain primary human oral keratinocytes as a small-sized, undifferentiated cell population capable of retaining their proliferative capacity. Primary, rapamycin-treated (2 nM, 20 nM) oral keratinocytes showed a diminished cell size that correlated with a higher clonogenicity, a longer-term proliferative potential, and a slower cycling cell population concurrent with decreased expression of a differentiation marker when compared with untreated cells. Only the 2-nM rapamycin-treated oral keratinocytes maintained their ability to regenerate oral mucosa in vitro after 15 weeks of culture. Rapamycin, a Food and Drug Administration-approved drug, may have applicability for use in creating a highly proliferative cell population for use in regenerative medicine.

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Section: Discussionmentioning

confidence: 77%

Pharmacological Retention of Oral Mucosa Progenitor/Stem Cells

et al. 2009

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“…Conversely, Gutkind and colleagues have used head and neck squamous cell carcinoma (HNSCC) cells expressing either WT mTOR or rapamycin-resistant mTOR to determine that mTORC1 inhibition in the tumor itself is necessary for the efficacy of rapamycin. 38 Therefore, in some situations, rapamycin must inhibit mTORC1 directly in the tumor. However, cell-autonomous and non-cell-autonomous mechanisms could both be involved, as the vasculature may be important for increased oxygen and glucose flow to the tumors, while upregulation of translationally controlled proteins like HIF-1α may allow some of these tumors to live in hypoxic environments through glycolytic addiction.…”

Section: Implications For Rapamycin-based Cancer Therapymentioning

confidence: 99%

Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapy

Choo¹,

Blenis²

2009

Cell Cycle

197

146

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The mTORC1 signaling pathway is a critical regulator of cell growth and is hyper activated in many different cancers. Rapamycin, an allosteric inhibitor of mTORC1, has been approved for treatment against renal cell carcinomas and is being evaluated for other cancers. Mechanistically, mTORC1 controls cell growth in part through its two well-characterized substrates S6K1 and 4E-BP1. In this review, we discuss the implications of a recent finding that showed differential inhibition of S6K1 and 4E-BP1 by rapamycin, leading to cell-type-specific repression of cap-dependent translation. We discuss potential mechanisms for this effect, and propose that mTOR-specific kinase inhibitors, instead of rapamycin, should be considered for mTOR-targeted cancer therapy.

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“…For the analysis of the effect of rapamycin on tumor development, mice (10 mice per group) were exposed to the carcinogen for 16 wk, examined, and randomly distributed into treatment and control groups, which received daily i.p. injections with rapamycin (5 mg/kg/d) or an equal volume of diluent (an aqueous solution of 5.2% Tween 80 and 5.2% polyethylene glycol), respectively, as previously described (14). In this regard, recently available evidence suggests that lower doses of rapamycin may be sufficient to block mTOR activity in tumor tissues in vivo (15,16), hence suggesting that lower doses of rapamycin may be considered for future analysis in this animal model of oral cancer.…”

Section: Experimental Modelmentioning

confidence: 99%

Targeting Mammalian Target of Rapamycin by Rapamycin Prevents Tumor Progression in an Oral-Specific Chemical Carcinogenesis Model

Czerninski

Amornphimoltham²,

Patel³

et al. 2009

Cancer Prevention Research

Self Cite

125

137

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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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A Retroinhibition Approach Reveals a Tumor Cell–Autonomous Response to Rapamycin in Head and Neck Cancer

Abstract: Emerging evidence supporting the activation of the Aktmammalian target of rapamycin (mTOR) signaling network in head and neck squamous cell carcinoma (HNSCC) progression has provided the rationale for exploring the therapeutic potential of inhibiting this pathway for HNSCC treatment.

Cited by 43 publications

References 46 publications

Pharmacological Retention of Oral Mucosa Progenitor/Stem Cells

Pharmacological Retention of Oral Mucosa Progenitor/Stem Cells

Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapy

Targeting Mammalian Target of Rapamycin by Rapamycin Prevents Tumor Progression in an Oral-Specific Chemical Carcinogenesis Model

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