Emerging Roles for Mammalian Target of Rapamycin (mTOR) Complexes in Bladder Cancer Progression and Therapy

Abstract

The mammalian target of rapamycin (mTOR) pathway regulates important cellular functions. Aberrant activation of this pathway, either through upstream activation by growth factors, loss of inhibitory controls, or molecular alterations, can enhance cancer growth and progression. Bladder cancer shows high levels of mTOR activity in approximately 70% of urothelial carcinomas, suggesting a key role for this pathway in this cancer. mTOR signaling initiates through upstream activation of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) and results in activation of either mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). While these complexes share several key protein components, unique differences in their complex composition dramatically alter the function and downstream cellular targets of mTOR activity. While significant work has gone into analysis of molecular alterations of the mTOR pathway in bladder cancer, this has not yielded significant benefit in mTOR-targeted therapy approaches in urothelial carcinoma to date. New discoveries regarding signaling convergence onto mTOR complexes in bladder cancer could yield unique insights the biology and targeting of this aggressive disease. In this review, we highlight the functional significance of mTOR signaling in urothelial carcinoma and its potential impact on future therapy implications.

Keywords: bladder cancer; inhibitor; invasion; mTOR; progression; targeted therapy; urothelial carcinoma.

Figure 1

Histology of urothelium. (A) Normal urothelium is a polarized epithelial lining containing urothelial cells and surface umbrella cells; the urothelial lining is polarized, with a relatively uniform nuclear size, open chromatin, and limited to rare mitotic figures (200×). (B) Low-grade papillary urothelial carcinoma is a papillary neoplasm with thin fibrovascular cores lined by relatively polarized urothelium containing occasional hyperchromatic nuclei (100×). (C) High-grade papillary urothelial carcinoma, another papillary neoplasm, shows cellular disorganization and enlarged hyperchromatic nuclei with nuclear pleomorphism and abnormal localization of mitotic figures (100×).

Figure 2

The cellular signaling and regulation of the mTOR pathway. Structurally, mTORC1 and mTORC2 share several protein components, including mTOR kinase, DEPTOR, and mLST8. Each complex also contains a couple of unique proteins. RAPTOR and PRSA40 are the components of mTORC1, where RICTOR and mSIN1 are the subunits of mTORC2. Both complexes integrate extracellular signaling through upstream PI3K/AKT and Ras/Raf/Mek/Erk signaling pathways to guide their own activation. mTORC1 is also regulated by the cellular status of amino acids, hypoxia, energetic stress, and DNA damage while mTORC2 mainly responds to growth factors. IRS, insulin receptor substrate; PI3K, phosphoinositide 3-kinases; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homologue; PDK1, phosphoinositide-dependent protein kinase-1; AKT, protein kinase B; mTOR, mammalian target of rapamycin; RAPTOR, regulatory-associated protein of mTOR; DEPTOR, DEP-domain-containing mTOR-interacting protein; PRAS40, proline-rich AKT substrate 40 kDa; mLST8, mammalian lethal with SEC13 protein 8; RICTOR, rapamycin-insensitive companion of mammalian target of rapamycin; PROTOR1/2, protein associated with rictor 1 or 2; mSIN1, MAPK-interacting protein 1; TSC1/TSC2, tuberous sclerosis complex 1, 2; Rheb, Ras homolog enriched in brain; AMPK, AMP-activated protein kinase; GATOR1/2, GAP activity towards the Rags 1,2; LKB1, liver kinase B1; Ras, rat sarcoma kinase; RAF, rapidly accelerated fibrosarcoma kinase; ERK, extracellular signal-regulated kinases, Mek, MAPK/ERK kinase; EGFR, epidermal growth factor receptor; REDD1, regulated in development and DNA damage responses 1.

Figure 3

The key downstream target molecules and function pathways of mTORC1. mTORC1 is a master regulator of cellular anabolism and promotes cell metabolism, growth, and proliferation by regulating a variety of downstream effectors, including mRNA translation; biosynthesis of proteins, nucleotides, and lipids; autophagy; lysosomal biogenesis; and angiogenesis. 4E-BP, 4E-binding protein; eIF-4E, eukaryotic translation initiation factor 4E; S6K1, p70 S6 kinase 1; eIF-A/B, eukaryotic translation initiation factor 4A/B; HIF1α, hypoxia-inducible factor 1α; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1-α; SREBP, sterol regulatory element-binding protein; PPARγ peroxisome proliferator-activated receptor-γ; TFEB, transcription factor EB; TFE3, transcription factor E3; ULK1, unc-51-like autophagy- activating kinase 1; ATG13, autophagy-related 13; AFT4, activating transcription factor 4.

Figure 4

The key downstream target molecules and function pathways of mTORC2. mTORC2 activates the AGC (protein kinase A/protein kinase G/protein kinase C) family kinases PKC, AKT, and SGK to regulate the cytoskeleton, metabolism, and ion transport and promote cell survival. PKC, protein kinase C; SGK, serum- and glucocorticoid-induced protein kinase; GSK3β, glycogen synthase kinase 3β; TSC2, tuberous sclerosis complex 2.