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Review
. 2018 Jan 12;10(1):18.
doi: 10.3390/cancers10010018.

mTOR Pathways in Cancer and Autophagy

Mathieu Paquette  1   2 , Leeanna El-Houjeiri  3   4 , Arnim Pause  5   6
Affiliations
Review

mTOR Pathways in Cancer and Autophagy

Mathieu Paquette et al. Cancers (Basel). .

Abstract

TOR (target of rapamycin), an evolutionarily-conserved serine/threonine kinase, acts as a central regulator of cell growth, proliferation and survival in response to nutritional status, growth factor, and stress signals. It plays a crucial role in coordinating the balance between cell growth and cell death, depending on cellular conditions and needs. As such, TOR has been identified as a key modulator of autophagy for more than a decade, and several deregulations of this pathway have been implicated in a variety of pathological disorders, including cancer. At the molecular level, autophagy regulates several survival or death signaling pathways that may decide the fate of cancer cells; however, the relationship between autophagy pathways and cancer are still nascent. In this review, we discuss the recent cellular signaling pathways regulated by TOR, their interconnections to autophagy, and the clinical implications of TOR inhibitors in cancer.

Keywords: autophagy; cancer; mTOR; signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic of key players in the mammalian autophagy pathway discussed in this review. The mechanistic target of rapamycin (mTORC1) is the major control complex for autophagy. A diverse range of signals, such as growth factors and amino acids, regulates mTORC1 by inhibiting the Tuberous sclerosis complex 1 and 2 (TSC1/2), thereby alleviating the inhibitory effect of TSC1/2 on the Ras homolog enriched in the brain (Rheb), which subsequently activates mTORC1. The AMP-activated protein kinase (AMPK) also inhibits mTORC1 via inhibition of the Regulatory associated protein of mTOR (Raptor). mTORC1 is tethered to the lysosomal surface via the Ras-related GTPases (Rags), which activity is regulated by the amino acid sensing of the the vacuolar H+-adenosine triphosphatase ATPase (v-ATPase) and the Proton-assisted amino acid transporter 1 (PAT1). Conversion of GTP-GDP is performed by the GTPase-activating proteins/ Guanine-exchange factor (GAP/GEF) activity of Folliculin (FLCN) and Ragulator. Under nutrient-rich conditions, mTORC1 suppresses autophagy by mediating phosphorylation-dependent inhibition of Unc-51 like autophagy activating kinase (ULK1) and the Transcription factor EB/E3 (TFEB/TFE3). Under starvation, ULK1 activation promotes autophagy initiation and autophagosome maturation, and TFEB/TFE3 promote transcription of genes regulating autophagy and lysosomal biogenesis.
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