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

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 (p21 Cip1 and p27 Kip1 ), 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.

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

“…Mutations in it are almost exclusively gain-of-function 50 and have been identified in about 12% of all human cancers. 51 They have specifically been found in breast, cervical, ovarian, gastric, colorectal, and lung, 20 and in up to 27% of UCCs. 49 A study evaluating renal and collecting system diseases found that PIK3CA mutations were specific to UCC of the renal pelvis as compared with other renal neoplasms such as renal cell carcinoma.…”

“…14,20 It regulates actin cytoskeleton remodeling, whereas mTORC1 is primarily responsible for nutrient and growth factor signal sensing. 14,[20][21][22] mTOR PATHWAY ACTIVATION mTOR is only one part of the larger phosphatidylinositol 3 kinase (PI3K)/Akt/mTOR pathway ( Figure 1). Upstream activation of this pathway begins when growth factors (insulin, insulin-like growth factor, platelet-derived growth factor), mitogens, hormones, or nutrients activate PI3K.…”

“…Upstream activation of this pathway begins when growth factors (insulin, insulin-like growth factor, platelet-derived growth factor), mitogens, hormones, or nutrients activate PI3K. 20,22,23 PI3K is a heterodimer that consists of a catalytic subunit (p110) and a regulatory subunit (p85, p55, or p50). 22 The activated p110 catalytic subunit, encoded by the PIK3CA gene, phosphorylates phosphatidylinositol bisphosphate 4,5 on the inner leaflet of the cytoplasmic membrane to generate phosphatidylinositol triphosphate (PIP3).…”

“…p70 S6K, a serine/threonine kinase, phosphorylates the ribosomal protein S6 of the 40S ribosomal subunit at Ser235 and 236 to increase translation of 5 0 terminal oligopyrimidine tract mRNAs 10 and also binds to mitochondrial membranes and inactivates the pro-apoptotic molecule BAD. 11,20 Phosphorylation of 4E-BP allows assembly of the translational initiation complex with subsequent translation of proteins necessary for progression of the cell cycle past the G1 phase, such as cyclin D1. 23,27,28 NEGATIVE REGULATION OF THE mTOR-SIGNALING PATHWAY PTEN is a tumor suppressor and lipid/protein phosphatase, mapped to chromosome 10, that is commonly mutated or lost in solid tumor malignancies.…”

The importance of the PI3K/AKT/mTOR signaling pathway in canine neoplasms: Literature review

“…Some studies suggest that these proteins are commonly activated in cancer cells, contributing to cell proliferation and carcinogenesis (Dancey and Sausville 2003, Dillon et al 2007, Jiang and Liu 2008.…”