Role of mTOR in anticancer drug resistance: Perspectives for improved drug treatment

https://doi.org/10.1016/j.drup.2008.03.001Get rights and content

Abstract

The mammalian target of rapamycin (mTOR) pathway plays a central role in regulating protein synthesis, ribosomal protein translation, and cap-dependent translation. Deregulations in mTOR signaling are frequently associated with tumorigenesis, angiogenesis, tumor growth and metastasis. This review highlights the role of the mTOR in anticancer drug resistance. We discuss the network of signaling pathways in which the mTOR kinase is involved, including the structure and activation of the mTOR complex and the pathways upstream and downstream of mTOR as well as other molecular interactions of mTOR. Major upstream signaling components in control of mTOR activity are PI3K/PTEN/AKT and Ras/Raf/MEK/ERK pathways. We discuss the central role of mTOR in mediating the translation of mRNAs of proteins related to cell cycle progression, those involved in cell survival such as c-myc, hypoxia inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF), cyclin A, cyclin dependent kinases (cdk1/2), cdk inhibitors (p21Cip1 and p27Kip1), retinoblastoma (Rb) protein, and RNA polymerases I and III. We then discuss the potential therapeutic opportunities for using mTOR inhibitors rapamycin, CCI-779, RAD001, and AP-23573 in cancer therapy as single agents or in combinations to reverse drug resistance.

Introduction

The mammalian target of rapamycin (mTOR, also known as rapamycin-associated protein [FRAP], rapamycin target [RAFT1], or sirolimus effector protein [SEP]) was identified and cloned shortly after the discovery of the two yeast genes, TOR1 and TOR2 (Brown et al., 1994, Chiu et al., 1994, Kunz et al., 1993, Sabatini et al., 1994). The structure of mTOR is highly conserved. Human mTOR has a 95% amino acid sequence identity to the mouse and rat TOR proteins. mTOR is a 289 kDa serine/threonine kinase and is a member of the large phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family and its catalytic kinase domain in the C-terminus is highly homologous to the lipid kinase domain of PI3K. The members of this family are involved in such basic cellular functions as cell proliferation, cell cycle progression, DNA damage checkpoints, and maintainance of telomere length. Dysfunction of PIKK-related kinases results in disorders such as cancer and immunodeficiency (Bjornsti and Houghton, 2004, Janus et al., 2005).

In cancer cells often receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) or insulin-like growth factor 1 receptor (IGF-1R) are aberrantly actived and may trigger multiple cytoplasmic kinases including serine/threonine kinases (Faivre et al., 2006). These cellular signaling pathways promote cancer development independently or in parallel and/or through cross-talk and involve frequently, the PI3K/AKT kinase pathway and mitogen-activated protein kinase (MAPK) cascades (Tortora et al., 2007). Both these signaling cascades can regulate the function of mTOR (Faivre et al., 2006, Shaw and Cantley, 2006).

The ability of cancer cells to become resistant to anticancer agents remains a significant impediment to successful chemotherapy. Multiple mechanisms have been shown to contribute to cancer cell drug resistance, including reduction of drug accumulation, increase of thiol-containing biomolecules such as glutathione and metallothioneins, enhancement of the DNA damage repair, and multiple deficiencies in apoptosis induction (Estrela et al., 2006, Madhusudan and Middleton, 2005, Mollinedo and Gajate, 2006, Yu, 2006, Fojo, 2007, Broxterman and Georgopapadakou, 2007). Recently, also mTOR signaling has been implicated not only in tumor development, but also in drug resistance against chemotherapy and radiotherapy (Beuvink et al., 2005) and targeting of mTOR with rapamycin or its analogs has been shown to inhibit tumor growth and render tumors sensitive to chemotherapy in vivo (Dudkin et al., 2001, Frost et al., 2004, Stephan et al., 2004). In this review, we highlight recent findings on the involvement of the mTOR signaling pathway in cancer cell survival, proliferation and drug resistance.

Section snippets

mTOR structure and activation

It has been shown that the TOR pathway is essential for cell growth and development in fruit flies, nematodes and mammals and dysfunction of the gene encoding TOR leads to lethality in all species. TOR regulates cellular functions, including translation, transcription, mRNA turnover, protein stability, actin cytoskeletal organization and autophagy (Inoki et al., 2005, Jacinto and Hall, 2003, Moretti et al., 2007).

Eukaryote TORs share 40–60% identity in their primary sequence. mTOR comprises

mTOR signaling and cancer

mTOR mediates the translation of mRNAs related with cell cycle check-points, regulates the expression of survival factors such as c-myc, HIF-1α and vascular endothelial growth factor (VEGF) and is involved in the regulation of cyclin A, cyclin dependent kinases (cdk1/2), cdk inhibitors (p21Cip1 and p27Kip1), retinoblastoma (Rb) protein, RNA polymerases, protein phosphatases (PP2A, PP4 and PP6) and CLIP-170. mTOR also plays a key role in regulating cancer cell proliferation, apoptosis, cell

mTOR inhibitors and tumor selectivity

Rapamycin (sirolimus) is a macrocyclic lactone product from the soil bacteria Streptomyces hygroscopicus. It was isolated and identified as an antifungal agent, especially active against Candida albicans. In the 1990s, it was approved by the FDA as an immunosuppressive agent. Later it was found to have antitumor and immunosupressive properties. Rapamycin and its analogs CCI-779 (temsirolimus), RAD001 (everolimus), and AP-23573 inhibit mTOR activation by binding to FK506-binding protein-12.

Conclusion and future directions

mTOR plays a central role in the cellular response to growth factors and receptor activation through PI3K/AKT and Raf/MEK signaling pathways and in the response to nutrients and stress through the AMPK/LKB1 signaling pathway. mTOR is involved in protein synthesis, cell proliferation, survival and multiple drug resistance mechansisms in cancer cells and upstream signaling molecules of mTOR including EGFR, IGF-1R, PI3K, PTEN, and AKT are frequently mutated in human cancer. Treatment with mTOR

Acknowledgements

This work was supported by CA109460 and CA123675 grants from National Cancer Institute, NIH; by American Cancer Society Research Scholar Grant 04-076-01-TBE.

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