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Mammalian target of rapamycin and head and neck squamous cell carcinoma.

Liao YM, Kim C, Yen Y - Head Neck Oncol (2011)

Bottom Line: Head and neck squamous cell carcinoma (HNSCC), a significant cause of cancer deaths worldwide, has multiple stepwise malignant evolutions.Mammalian target of rapamycin (mTOR) plays a critical role in tumor development, invasion, metastasis and angiogenesis that impact local recurrence and survival. mTOR can also act as a biomarker for personalized adjuvant therapy.In in vivo and in vitro studies, mTOR inhibitor suppresses tumor growth and sensitizes HNSCC to radiation, cytotoxic agents and epidermoid growth factor receptor inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.

ABSTRACT
Head and neck squamous cell carcinoma (HNSCC), a significant cause of cancer deaths worldwide, has multiple stepwise malignant evolutions. Mammalian target of rapamycin (mTOR) plays a critical role in tumor development, invasion, metastasis and angiogenesis that impact local recurrence and survival. mTOR can also act as a biomarker for personalized adjuvant therapy. In in vivo and in vitro studies, mTOR inhibitor suppresses tumor growth and sensitizes HNSCC to radiation, cytotoxic agents and epidermoid growth factor receptor inhibitors. We have reviewed the pathogenesis of HNSCC, mTOR pathway, mTOR inhibitor and the role of mTOR in HNSCC.

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Mammalian target of rapamycin is a key regulator in development and progression of cancer. Mammalian target of rapamycin responds to stimuli of growth factor, insulin, tobacco components, nutrients, hypoxia, ATP and RHEB to activate P70S6 and inhibit 4EBP1 and PP5 with subsequent dysregulation of apoptosis, cell survival, cell transformation, tumorigenesis, angiogenesis, invasion and metastasis. PI3K, phosphatidylinositol 3-kinase; ATP, adenosine triphosphate; RHEB, ras homologue enriched in brain; mTORC1, mammalian target of rapamycin complex 1; PP5, protein phosphatase 5; ASK1, apoptosis-signal-regulating kinase 1; p70S6, ribosomal p70 S6; EIF4E, eukaryotic translation initiation factor 4E; 4E-BP1, EIF4E-binding protein 1.
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Figure 1: Mammalian target of rapamycin is a key regulator in development and progression of cancer. Mammalian target of rapamycin responds to stimuli of growth factor, insulin, tobacco components, nutrients, hypoxia, ATP and RHEB to activate P70S6 and inhibit 4EBP1 and PP5 with subsequent dysregulation of apoptosis, cell survival, cell transformation, tumorigenesis, angiogenesis, invasion and metastasis. PI3K, phosphatidylinositol 3-kinase; ATP, adenosine triphosphate; RHEB, ras homologue enriched in brain; mTORC1, mammalian target of rapamycin complex 1; PP5, protein phosphatase 5; ASK1, apoptosis-signal-regulating kinase 1; p70S6, ribosomal p70 S6; EIF4E, eukaryotic translation initiation factor 4E; 4E-BP1, EIF4E-binding protein 1.

Mentions: Mammalian TOR (mTOR), a protein kinase encoded by FK506 binding protein 12-rapamycin associated protein 1 (FRAP1) gene[32]., is an important downstream target signal of PI3K pathway. (Figure 1) [33]. The protein contains an 12-kDa FK506-binding protein (FKBP12), rapamycin binding domain, Huntington Elongation Factor 3 PR65/ATOR (HEAT) motifs, FK506 binding protein 12-rapamycin associated protein (FRAP1)-ataxia telangiectasia mutated (ATM)-transformation transcription domain-associated protein (FAT) and FAT C terminus (FATC) domain. In terms of structure and function, mTOR consists of two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)[34,35]. mTOR, regulatory-associated protein of mTOR (Raptor) and G-protein-subunit-like protein form mTORC1, a nutrition-sensitive complex. mTORC1 is sensitive to rapamycin, control cell growth and is a key factor of the mTOR pathway[34-38]. mTORC2, a complex containing mTOR, G-protein-subunit-like protein and mAVO3, regulates the actin cytoskeleton and is insensitive to rapamycin[39]. As an important target kinase of the PI3K pathway, mTOR responds to multiple stimuli including: nutrients, insulin, oxygen, growth factor, ATP, Ras homologue enriched in brain (RHEB) and tobacco components[33,38,40-44]. However, mTOR is negatively regulated by complex of tuberin and hamartin[45]. Through the activation of two downstream targets p70S6K and 4EBP1, mTOR functions on translation, cell growth, protein synthesis, cell size and angiogenesis[46-48]. Activated p70S6K stimulates 5-terminal oligopyrimidine (5'TOG) translation to regulate ribosome biogenesis[49]. Phosphorylated 4EBP1 disassociates with eIF4E. The free eIF4E, an oncoprotein, promotes cap-dependent translation with subsequent regulation of c-myc, cyclin D1, ornithinedecarboxylase, basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) to affect cell survival, tumorigenesis and transformation, angiogenesis, invasion and metastasis[41,50-54]. In addition, mTOR-enhanced expression of HIF-1a protein, HIF-1 transcriptional activity, and VEGF protein are the key regulators in angiogenesis[55]. Apoptosis signal-regulating kinase 1 (ASK1)-modulated apoptosis can be inhibited by mTOR-induced overexpression of protein phosphatase 5 (PP5)[56].


Mammalian target of rapamycin and head and neck squamous cell carcinoma.

Liao YM, Kim C, Yen Y - Head Neck Oncol (2011)

Mammalian target of rapamycin is a key regulator in development and progression of cancer. Mammalian target of rapamycin responds to stimuli of growth factor, insulin, tobacco components, nutrients, hypoxia, ATP and RHEB to activate P70S6 and inhibit 4EBP1 and PP5 with subsequent dysregulation of apoptosis, cell survival, cell transformation, tumorigenesis, angiogenesis, invasion and metastasis. PI3K, phosphatidylinositol 3-kinase; ATP, adenosine triphosphate; RHEB, ras homologue enriched in brain; mTORC1, mammalian target of rapamycin complex 1; PP5, protein phosphatase 5; ASK1, apoptosis-signal-regulating kinase 1; p70S6, ribosomal p70 S6; EIF4E, eukaryotic translation initiation factor 4E; 4E-BP1, EIF4E-binding protein 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108931&req=5

Figure 1: Mammalian target of rapamycin is a key regulator in development and progression of cancer. Mammalian target of rapamycin responds to stimuli of growth factor, insulin, tobacco components, nutrients, hypoxia, ATP and RHEB to activate P70S6 and inhibit 4EBP1 and PP5 with subsequent dysregulation of apoptosis, cell survival, cell transformation, tumorigenesis, angiogenesis, invasion and metastasis. PI3K, phosphatidylinositol 3-kinase; ATP, adenosine triphosphate; RHEB, ras homologue enriched in brain; mTORC1, mammalian target of rapamycin complex 1; PP5, protein phosphatase 5; ASK1, apoptosis-signal-regulating kinase 1; p70S6, ribosomal p70 S6; EIF4E, eukaryotic translation initiation factor 4E; 4E-BP1, EIF4E-binding protein 1.
Mentions: Mammalian TOR (mTOR), a protein kinase encoded by FK506 binding protein 12-rapamycin associated protein 1 (FRAP1) gene[32]., is an important downstream target signal of PI3K pathway. (Figure 1) [33]. The protein contains an 12-kDa FK506-binding protein (FKBP12), rapamycin binding domain, Huntington Elongation Factor 3 PR65/ATOR (HEAT) motifs, FK506 binding protein 12-rapamycin associated protein (FRAP1)-ataxia telangiectasia mutated (ATM)-transformation transcription domain-associated protein (FAT) and FAT C terminus (FATC) domain. In terms of structure and function, mTOR consists of two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)[34,35]. mTOR, regulatory-associated protein of mTOR (Raptor) and G-protein-subunit-like protein form mTORC1, a nutrition-sensitive complex. mTORC1 is sensitive to rapamycin, control cell growth and is a key factor of the mTOR pathway[34-38]. mTORC2, a complex containing mTOR, G-protein-subunit-like protein and mAVO3, regulates the actin cytoskeleton and is insensitive to rapamycin[39]. As an important target kinase of the PI3K pathway, mTOR responds to multiple stimuli including: nutrients, insulin, oxygen, growth factor, ATP, Ras homologue enriched in brain (RHEB) and tobacco components[33,38,40-44]. However, mTOR is negatively regulated by complex of tuberin and hamartin[45]. Through the activation of two downstream targets p70S6K and 4EBP1, mTOR functions on translation, cell growth, protein synthesis, cell size and angiogenesis[46-48]. Activated p70S6K stimulates 5-terminal oligopyrimidine (5'TOG) translation to regulate ribosome biogenesis[49]. Phosphorylated 4EBP1 disassociates with eIF4E. The free eIF4E, an oncoprotein, promotes cap-dependent translation with subsequent regulation of c-myc, cyclin D1, ornithinedecarboxylase, basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) to affect cell survival, tumorigenesis and transformation, angiogenesis, invasion and metastasis[41,50-54]. In addition, mTOR-enhanced expression of HIF-1a protein, HIF-1 transcriptional activity, and VEGF protein are the key regulators in angiogenesis[55]. Apoptosis signal-regulating kinase 1 (ASK1)-modulated apoptosis can be inhibited by mTOR-induced overexpression of protein phosphatase 5 (PP5)[56].

Bottom Line: Head and neck squamous cell carcinoma (HNSCC), a significant cause of cancer deaths worldwide, has multiple stepwise malignant evolutions.Mammalian target of rapamycin (mTOR) plays a critical role in tumor development, invasion, metastasis and angiogenesis that impact local recurrence and survival. mTOR can also act as a biomarker for personalized adjuvant therapy.In in vivo and in vitro studies, mTOR inhibitor suppresses tumor growth and sensitizes HNSCC to radiation, cytotoxic agents and epidermoid growth factor receptor inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.

ABSTRACT
Head and neck squamous cell carcinoma (HNSCC), a significant cause of cancer deaths worldwide, has multiple stepwise malignant evolutions. Mammalian target of rapamycin (mTOR) plays a critical role in tumor development, invasion, metastasis and angiogenesis that impact local recurrence and survival. mTOR can also act as a biomarker for personalized adjuvant therapy. In in vivo and in vitro studies, mTOR inhibitor suppresses tumor growth and sensitizes HNSCC to radiation, cytotoxic agents and epidermoid growth factor receptor inhibitors. We have reviewed the pathogenesis of HNSCC, mTOR pathway, mTOR inhibitor and the role of mTOR in HNSCC.

Show MeSH
Related in: MedlinePlus