mTOR signaling: implications for cancer and anticancer therapy

Abstract

Mounting evidence links deregulated protein synthesis to tumorigenesis via the translation initiation factor complex eIF4F. Components of this complex are often overexpressed in a large number of cancers and promote malignant transformation in experimental systems. mTOR affects the activity of the eIF4F complex by phosphorylating repressors of the eIF4F complex, the eIF4E binding proteins. The immunosuppressant rapamycin specifically inhibits mTOR activity and retards cancer growth. Importantly, mutations in upstream negative regulators of mTOR cause hamartomas, haemangiomas, and cancers that are sensitive to rapamycin treatment. Such mutations lead to increased eIF4F formation and consequently to enhanced translation initiation and cell growth. Thus, inhibition of translation initiation through targeting the mTOR-signalling pathway is emerging as a promising therapeutic option.

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

“…Fresh fragments of tumor, tumor-like lesions, and non-neoplastic tissues were obtained from 34 (11) 9 (7) 5 (4) 3 (2) 8 (5) 9 (8) Liposarcoma (12) Well differentiated (5) 1 (0) 2 (1) 0 0 2 (0) Myxoid/round (7) 3 (1) 5 (4) 0 5 (3) 3 (2) Osteosarcoma (14) Osteoblastic 11 (7) 3 (2) 0 13 (11) 11 (7) Synovial sarcoma (8) Biphasic (1) 1 (1) 1 (1) 1 (1) 0 0 Monophasic (7) 4 (3) 7 (7) 6 (6) 4 (4) 1 (1) Dermatofibrosarcoma protuberans (4) (11) 4 (1) 8 (7) 0 7 (6) 9 (5) Rhabdomyosarcoma (6) 4 (4) 6 (6) 5 (3) 6 (4) 4 (4) Primitive neuroectodermal tumor (4) 3 (2) 4 (2) 1 (0) 4 (2) 4 (3) Chordoma (5) 4 (3) 5 (5) 5 (4) 5 (4) 4 (4) Angiosarcoma (2) 1 (0)…”

“…8,10,11 However, Akt could also directly phosphorylate mTOR on Ser 2448 . 12 mTOR is a 289 kD serine/threonine protein kinase, 13,14 activation of which positively regulates cell proliferation by promoting the G1/S phase transition of the cell cycle. This occurs through phosphorylation of two substrates, p70S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), that cooperate in translational initiation.…”

“…This occurs through phosphorylation of two substrates, p70S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), that cooperate in translational initiation. 8,14,15 This paradigm of kinase-driven pathway leading to phosphorylation of mTOR and promotion of cell proliferation constitutes a critical mechanism underlying the pathology of tumor growth. Indeed, aberrant activation of mTOR has been shown in several cancers, including kidney, breast, and the head and neck carcinomas.…”

“…One agent, the bacterial macrolide rapamycin, which inhibits mTOR activity, has emerged as a validated novel anticancer therapeutic. 8,14 In vitro studies have already established the potential of rapamycin in inhibiting cellular transformation and several kinds of tumors exhibiting activation of PI3-K/Akt are hypersensitive to rapamycin in vivo. 18,19 Recent preclinical evidence supports the efficiency of mTOR inhibitors in the treatment of sarcomas: rapamycin treatment resulted in reduced phosphorylation of proteins functioning downstream of mTOR and can greatly reduce the growth of cell lines from rhabdomyosarcoma, osteosarcoma, and Ewing sarcoma.…”

Biosynthesis of rapamycin and its regulation: past achievements and recent progress

“…33 The effects of rapamycin are not only limited to T-cell proliferation, but also include the proliferation of B lymphocytes. 34 In addition to its antifungal and anti-immunosuppressive effects, rapamycin and its derivatives, such as deferolimus (AP23537; 5), everolimus (RAD001; 6) and temsirolimus (CCl779; 7) shown in 35,36 It has also been shown that rapamycin and its analogs effectively suppress cellular proliferation and angiogenesis in a number of human malignancies. 37,38 More recently, it was reported that eukaryotic translation initiation factor 4E-binding proteins activation in vivo by rapamycin ( Figure 2) prevented dopaminergic neuron loss, 39 which is characteristic of the neurodegenerative disorder parkinsonism.…”