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.

The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways

“…53,54 The mammalian target of rapamycin (mTOR) pathway was shown to be overactivated in HNSCC by investigating Functional significance of miR-375 in human cancer T Kinoshita et al the phosphorylation status of the ribosomal protein S6, a well-known downstream target of mTOR. 55 These genes have been used to develop molecularly targeted therapeutic agents for human cancer, such as Gefinitib (Iressa, also known as ZD1839), Erlotinib (marketed as Tarceva) and Cetuximab (marketed as Erbitux), which target epidermal growth factor receptor 56 , and Everolimus (marketed as Afinitor) and Temsirolimus (marketed as Torisel), which target mTOR. 57 Cetuximab received Food and Drug Administration approval for treatment of locally advanced HNSCC in combination with radiotherapy.…”

Análise da expressão e mecanismos de ação das proteínas Akt, Hsp90, mTOR e ciclina D1 em cultura de células de carcinoma epidermoide humano e células displásicas após irradiação com laser em baixa intensidade

“…Este mesmo aumento de expressão em células de CECP também indicariam uma pior evolução da lesão, uma vez que carcinomas que apresentam altos níveis destes marcadores geralmente são relacionados a um pior prognóstico (39,40,138,147,148) .…”

“…Assim, o acúmulo da forma fosforilada da proteína S6, último alvo downstream da via Akt-mTOR-p70S6K, é frequentemente encontrado em espécimes clínicos de pacientes com carcinoma de cabeça e pescoço e linhagens celulares derivadas da mesma patologia (39) .…”

“…Outros estudos identificaram altos níveis de pS6 em uma fração considerável de amostras clínicas e linhagens celulares de CECP (39,138) , mostrando que a inibição do mTOR pela rapamicina diminui os níveis de pS6 e causa morte por apoptose em enxertos xenógenos de CECP (39,138) . Estudos recentes mostraram que a depleção de S6 leva à indução de p53, o que resulta na interrupção do ciclo celular em hepatócitos (141) , sugerindo que S6 ajuda a regular o ciclo celular.…”

“…Assim, a fosforilação do Akt é um evento muito importante na patogênese do carcinoma de cabeça e pescoço (38,39) . Esta fosforilação tem sido detectada em aproximadamente 50% das lesões pré-neoplásicas de língua e indica um pior 26 prognóstico destas lesões (40) .…”