Targeting mTOR network in colorectal cancer therapy

Abstract

The mechanistic target of rapamycin (mTOR) integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth, proliferation and survival. A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division. Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate. Multiple genetic alterations are involved in colorectal carcinogenesis, including oncogenic Ras activation, phosphatidylinositol 3-kinase pathway hyperactivation, p53 mutation, and dysregulation of wnt pathway. Many oncogenic pathways activate the mTOR pathway. mTOR has emerged as an effective target for colorectal cancer therapy. In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives. However, the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest, especially in advanced metastatic colorectal cancer. Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy, inhibitors of vascular endothelial growth factor, epidermal growth factor receptor and Mitogen-activated protein kinase kinase (MEK) inhibitors are being intensively studied and appear to be promising. Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens. In this paper, oncogenic gene alterations in colorectal cancer, as well as their interaction with the mTOR pathway, are systematically summarized. The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed. New players in mTOR signaling pathway, such as non-steroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.

The mTOR Signalling Pathway in Cancer and the Potential mTOR Inhibitory Activities of Natural Phytochemicals

“…The mTOR pathway is a key regulator of cell proliferation and several upstream activators and downstream effectors of mTOR are known to be deregulated in some cancers such as renal cell carcinoma, non-small cell lung cancer, breast cancer, sarcomas, colorectal and gastrointestinal tumors (Law, 2005;Tokunaga et al, 2008;Li et al, 2013;Takahashi et al, 2014;Wang and Zhang, 2014). The mTOR signalling is constitutively activated in many tumor types, suggesting that mTOR is an attractive target for cancer drug development and therapy (Yu et al, 2001;Chan, 2004;Shor et al, 2009;Han et al, 2013;Pandurangan, 2013).…”

Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytesin vitrovia mTOR-signaling pathway

“…The mTOR pathway has been identified as a key intracellular signaling pathway for important cellular functions. It regulates cell growth and proliferation largely by promoting key anabolic processes, sensing nutrition levels and growth factors, as well as responding to various environmental cues (Wang & Zhang, 2014). mTOR has been implicated in the development and progression of various skin diseases including melanoma, acne vulgaris, and psoriasis.…”

4E-BP1, a multifactor regulated multifunctional protein

“…1 It is a PI3K-related kinase that forms two distinct protein complexes called mTOR complex 1 or mTORC1 and mTOR complex 2 or mTORC2. In response to upstream stimuli, mTORC1 phosphorylates S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) to stimulate protein synthesis, 2 while mTORC2 phosphorylates AKT to promote cell survival.…”